Phosphatidylinositol 3-kinase inhibitors

ABSTRACT

The present application provides the compounds of formula (J), 
     
       
         
         
             
             
         
       
     
     or pharmaceutically acceptable salts, isomers, tautomer, or a mixture thereof, wherein X, Y, Z, n, m′, A′, R 1 , R 2 , and R 3  are described herein. The compounds are inhibitors to the activities of phosphatidylinositol 3-kinase (PI3K) and are useful for treating conditions mediated by one or more PI3K isoforms. The present application further provides pharmaceutical compositions that include a compound of formula (I), or pharmaceutically acceptable salts, isomers, tautomer, or mixture thereof, and methods of using these compounds and compositions for treating conditions mediated by one or more PI3K isoforms.

This application claims the benefit and the priority of U.S. provisional patent application Ser. No. 62/011,775, filed Jun. 13, 2014, the disclosure is incorporated herein by reference in its entirety.

FIELD

The present application relates to novel compounds that selectively inhibit the activities of PI3K isoforms and their uses in therapeutic treatments.

BACKGROUND

Cell signaling via 3′-phosphorylated phosphoinositides has been implicated in a variety of cellular processes, e.g., malignant transformation, growth factor signaling, inflammation, and immunity (Rameh et al., J. Biol. Chem., 274:8347-8350, 1999). Phosphatidylinositol 3-kinase (PI 3-kinase or PI3K) is responsible for generating these phosphorylated signaling products. PI3K was initially identified as a protein associated with viral oncoproteins and growth factor receptor tyrosine kinases that phosphorylate phosphatidylinositol (PI) and its phosphorylated derivatives at the 3′-hydroxyl of the inositol ring (Panayotou et al., Trends Cell Biol., 2:358-60, 1992).

Three classes of the PI 3-kinase (PI3K) are proposed based on the substrate specificities. Class I PI3Ks phosphorylate phosphatidylinositol (PI), phosphatidylinositol-4-phosphate, and phosphatidylinositol-4,5-biphosphate (PIP₂) to produce phosphatidylinositol-3-phosphate (PIP), phosphatidylinositol-3,4-biphosphate, and phosphatidylinositol-3,4,5-triphosphate, respectively. Also, Class II PI3Ks phosphorylate PI and phosphatidylinositol-4-phosphate, and Class III PI3Ks phosphorylate PI.

The initial purification and molecular cloning of PI 3-kinase revealed that it was a heterodimer consisting of p85 and p110 subunits (Otsu et al., Cell, 65:91-104, 1991; Hiles et al., Cell, 70:419-29, 1992). Later, four distinct Class I PI3Ks were identified and designated as PI3K α, β, δ, and γ isoforms. Each isoform consists of a distinct 110 kDa catalytic subunit and a regulatory subunit. The catalytic subunits of PI3K α, β, and δ (i.e., p110α, p110β, and p110δ, respectively) interacts, individually, with the same regulatory subunit p85, whereas the catalytic subunit of PI3K γ (p110γ) interacts with a distinct regulatory subunit p101.

Studies have also showed that each PI3K isoform has distinct expression pattern. For example, PIK3CA which encodes PI3Kα is frequently mutated in human cancers (Engelman, Nat. Rev. Cancer, 9: 550-562, 2009). Also, PI3Kδ is generally expressed in hematopoietic cells. Moreover, PI3K isoforms are shown to be associated with proliferation or survival signaling in cancers, inflammatory, or autoimmune diseases. As each PI3K isoform has different biological function, PI3K isoforms are potential targets to treat cancer or disorder (U.S. Pat. Nos. 6,800,620; 8,435,988; 8,673,906; US Patent Application Publication No. US2013/0274253).

Therefore, there is a need for developing therapeutic agents that inhibit PI3K isoforms to treat diseases, disorders, or conditions that are mediated by PI3K.

SUMMARY

The present application provides novel compounds that are inhibitors of PI3K isoforms. The application also provides compositions, including pharmaceutical compositions, kits that include the compounds, and methods of using and making the compounds. The compounds provided herein are useful in treating diseases, disorders, or conditions that are mediated by PI3K isoforms. The application also provides compounds for use in therapy. The application further provides compounds for use in a method of treating a disease, disorder, or condition that is mediated by PI3K isoforms. Moreover, the application provides uses of the compounds in the manufacture of a medicament for the treatment of a disease, disorder or condition that is mediated by PI3K isoforms.

The applications provides the compounds having the structure of formula (I):

wherein:

X, Y and Z are independently selected from C(R′) or N, wherein at least one of X, Y, and Z is C(R′);

n is 0, 1, 2, 3, or 4;

m′ is 0 or 1;

A is a single bond or C(O);

each R′ is independently selected from hydrogen, halo, optionally substituted alkyl, optionally substituted haloalkyl, and optionally substituted cycloalkyl;

each R¹ is independently selected from halo, cyano, optionally substituted C₁₋₆ alkyl, optionally substituted C₁₋₆ alkoxy, hydroxy, optionally substituted C₃₋₈ cycloalkyl, and optionally substituted sulfonyl;

each R² is independently selected from halo, optionally substituted C₁₋₆ alkyl, optionally substituted C₁₋₆ haloalkyl, and optionally substituted C₃₋₈ cycloalkyl;

R³ is hydrogen, optionally substituted C₁₋₆ alkyl, optionally substituted C₃₋₈ cycloalkyl, or optionally substituted C₆₋₁₀ aryl;

R⁴ is a six- to twelve-membered heteroaryl having at least two heteroatoms, wherein each heteroatom is independently selected from N, O, or S, wherein the heteroaryl is optionally substituted with one, two, or three members independently selected from halo, cyano, —NH₂, optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkynyl; and

R⁵ is hydrogen or optionally substituted C₁₋₆ alkyl; R⁵ and R³ together with the atoms to which they are attached optionally form a four- to eight-membered heterocyclic ring;

or a pharmaceutically acceptable salt, isomer, or a mixture thereof.

In one aspect, the compound of the present application having the structure of formula (I), wherein:

A is a single bond or C(O);

each R′ is independently selected from hydrogen, halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, or C₃₋₆ cycloalkyl, wherein the alkyl moiety is optionally substituted with C₁₋₄ alkoxy;

each R¹ is independently selected from halo, cyano, C₁₋₄ alkyl, C₁₋₄ haloalkyl, or —SO₂C₁₋₄ alkyl;

each R² is independently selected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, or C₃₋₆ cycloalkyl, wherein the alkyl moiety is optionally substituted with C₁₋₄ alkoxy;

R³ is hydrogen, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, or C₆₋₁₀ aryl; wherein the alkyl moiety is optionally substituted with hydroxyl or C₁₋₄ alkoxy, wherein C₁₋₄ alkoxy is optionally substituted with C₆₋₁₀ aryl;

R⁴ is a six- to twelve-membered heteroaryl having at least one aromatic ring and at least two nitrogen atoms, wherein the heteroaryl is optionally substituted with one, two, or three members independently selected from halo, cyano, —NH₂, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, and C₁₋₄ alkyl, wherein the C₂₋₄ alkynyl moiety is optionally substituted with C₆₋₁₀ aryl or C₃₋₈ heteroaryl, wherein each of the C₆₋₁₀ aryl and C₃₋₈ heteroaryl moieties is optionally substituted with one, two, or three members independently selected from halo and C₁₋₆ haloalkyl;

R⁵ is hydrogen or C₁₋₄ alkyl; R⁵ and R³ together with the nitrogen to which they are attached optionally form a five-membered heterocyclic ring;

or a pharmaceutically acceptable salt, isomer, or a mixture thereof.

In another aspects, the compound of the present application having the structure of formula (I), wherein each R¹ is selected from fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, butyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, cyano, methylsulfonyl, and ethylsulfonyl. In other aspects, each R² is selected from hydrogen, fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, butyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, methoxymethyl, methoxyethyl, ethoxymethyl, methoxypropyl, ethoxyethyl, ethoxypropyl, cyclopropyl, and cyclobutyl. In some aspects, the compound of the present application having the structure of formula (I), wherein R³ is selected from methyl, ethyl, propyl, cyclopropyl, cyclobutyl, phenyl, benzyloxymethyl, benzyloxyethyl, benzyloxypropyl, —CH₂OH, —C₂H₄OH, or —C₃H₆OH. In certain aspect, R⁵ is selected from hydrogen, methyl, ethyl, or propyl. In additional aspects, R³ and R⁵ together with the atoms to which they are attached optionally form pyrrolidinyl. In some aspects, wherein R⁴ is a monocyclic heteroaryl having at least two nitrogen atoms, wherein R⁴ is optionally substituted with two to three members independently selected from the group consisting of halo, cyano, —NH₂, C₁₋₄ alkyl, and optionally substituted C₂₋₄ alkynyl. In some other aspects, R⁴ is a bicyclic heteroaryl having at least one aromatic ring, at least two nitrogen atoms, and at least one additional heteroatom selected from N, O, or S, wherein R⁴ is optionally substituted with one, two, or three members independently selected from the group consisting of halo, cyano, —NH₂, and C₁₋₄ alkyl. In further aspects, R⁴ is selected from purinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolopyrimidinyl, pyridopyrimidinyl, thienopyrimidinyl, pyrrolopyrimidinyl, furopyrimidinyl, or imidazotriazinyl; wherein each moiety is optionally substituted with one, two, or three members selected from the group consisting of halo, cyano, —NH₂, C₁₋₄ alkyl, C₂₋₄ alkynyl, wherein the C₂₋₄ alkynyl moiety is optionally substituted with C₆₋₁₀ aryl or C₄₋₈ heteroaryl, wherein each of the C₆₋₁₀ aryl or C₃₋₈ heteroaryl moieties is optionally substituted with one, two, or three members independently selected from fluoro, chloro, bromo, iodo, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, and trifluoroethyl.

In certain embodiments, the PI3K inhibitors are the compounds selected from Table 1, a pharmaceutically acceptable salt, isomer, or a mixture thereof. In some embodiments, the PI3K inhibitors are the compounds selected from Table 1a, a pharmaceutically acceptable salt, isomer, or a mixture thereof. In additional embodiments, the compound is an (S)-enantiomer. In other embodiments, the compound is an (R)-enantiomer. In other additional embodiments, the compound is an atropisomer.

The application also provides a pharmaceutical composition that comprises a compound of formula (I), a pharmaceutically acceptable salt, isomer, or a mixture thereof, together with at least one pharmaceutically acceptable vehicle. Examples of a pharmaceutically acceptable vehicle may be selected from carriers, adjuvants, and excipients.

Further provided herein is a method of treating a disease, disorder, or condition in a human in need thereof by administering to the human a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, isomer, or a mixture thereof. Further provided is a compound of formula (I) for use in a method of treating a disease, disorder or condition that is mediated by PI3K isoforms. The application also provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment of a disease, disorder or condition that is mediated by PI3K isoforms. In certain embodiments, the disease, disorder, or condition is associated or mediated by PI3K. In some embodiments, the disease, disorder, or condition is an inflammatory disorder. In other embodiments, the disease, disorder, or condition is a cancer.

Also provided herein is a method of inhibiting the activity of a phosphatidylinositol 3-kinase polypeptide by contacting the polypeptide with a compound of formula (I) or a pharmaceutically acceptable salt, isomer, or a mixture thereof.

Further provided is a method of inhibiting excessive or destructive immune reactions, comprising administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, isomer, or a mixture thereof.

Also provided is a method of inhibiting growth or proliferation of cancer cells comprising contacting the cancer cells with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, isomer, or a mixture thereof.

Also provided is a kit that includes a compound of formula (I) or a pharmaceutically acceptable salt, isomer, or a mixture thereof. The kit may further comprise a label and/or instructions for use of the compound in treating a disease, disorder, or condition in a human in need thereof. In some embodiments, the disease, disorder, or condition may be associated or mediated by PI3K activity.

Also provided are articles of manufacture that include a compound of formula (I) or a pharmaceutically acceptable salt, isomer, or a mixture thereof, and a container. In one embodiment, the container may be a vial, jar, ampoule, preloaded syringe, or an intravenous bag.

DETAILED DESCRIPTION

The following description sets forth exemplary methods, parameters and the like. Such description is not intended as a limitation on the scope of the present application but is instead provided as exemplary embodiments.

As used herein, the following words, phrases and symbols are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.

A dash (“-”) that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, —CONH₂ is attached through the carbon atom. A dash at the front or end of a chemical group is a matter of convenience; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning. A wavy line drawn through a line in a structure indicates a point of attachment of a group. Unless chemically or structurally required, no directionality is indicated or implied by the order in which a chemical group is written or named.

The prefix “C_(u-v)” indicates that the following group has from u to v carbon atoms. For example, “C₁₋₆ alkyl” indicates that the alkyl group has from 1 to 6 carbon atoms.

Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. In certain embodiments, the term “about” includes the indicated amount ±10%. In other embodiments, the term “about” includes the indicated amount ±5%. In certain other embodiments, the term “about” includes the indicated amount ±1%. Also, to the term “about X” includes description of “X”. Also, the singular forms “a” and “the” include plural references unless the context clearly dictates otherwise. Thus, e.g., reference to “the compound” includes a plurality of such compounds and reference to “the assay” includes reference to one or more assays and equivalents thereof known to those skilled in the art.

“Alkyl” refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl has 1 to 20 carbon atoms (i.e., C₁₋₂₀ alkyl), 1 to 8 carbon atoms (i.e., C₁₋₈ alkyl), 1 to 6 carbon atoms (i.e., C₁₋₆ alkyl), or 1 to 4 carbon atoms (i.e., C₁₋₄ alkyl). Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a specific number of carbons is named, all geometric isomers having that number of carbons may be encompassed; thus, for example, “butyl” includes n-butyl, sec-butyl, isobutyl and t-butyl; “propyl” includes n-propyl and isopropyl.

“Alkenyl” refers to an aliphatic group containing at least one carbon-carbon double bond and having from 2 to 20 carbon atoms (i.e., C₂₋₂₀ alkenyl), 2 to 8 carbon atoms (i.e., C₂₋₈ alkenyl), 2 to 6 carbon atoms (i.e., C₂₋₆ alkenyl), or 2 to 4 carbon atoms (i.e., C₂₋₄ alkenyl). Examples of alkenyl groups include ethenyl, propenyl, butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

“Alkynyl” refers to an aliphatic group containing at least one carbon-carbon triple bond and having from 2 to 20 carbon atoms (i.e., C₂₋₂₀ alkynyl), 2 to 8 carbon atoms (i.e., C₂₋₈ alkynyl), 2 to 6 carbon atoms (i.e., C₂₋₆ alkynyl), or 2 to 4 carbon atoms (i.e., C₂₋₄ alkynyl). The term “alkynyl” also includes those groups having one triple bond and one double bond.

“Alkoxy” refers to the group “alkyl-O—”. Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

“Acyl” refers to a group —C(═O)R, wherein R is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein. Examples of acyl include formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl.

“Amido” refers to both a “C-amido” group which refers to the group —C(═O)NR^(y)R^(z) and an “N-amido” group which refers to the group —NR^(y)C(═O)R^(z), wherein R^(y) and R^(z) are independently selected from the group consisting of hydrogen, alkyl, aryl, haloalkyl, or heteroaryl; each of which may be optionally substituted.

“Amino” refers to the group —NR^(y)R^(z) wherein R^(y) and R^(z) are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl, or heteroaryl; each of which may be optionally substituted.

“Aryl” refers to an aromatic carbocyclic group having a single ring (e.g. monocyclic) or multiple rings (e.g. bicyclic or tricyclic) including fused systems. As used herein, aryl has 6 to 20 ring carbon atoms (i.e., C₆₋₂₀ aryl), 6 to 12 carbon ring atoms (i.e., C₆₋₁₂ aryl), or 6 to 10 carbon ring atoms (i.e., C₆₋₁₀ aryl). Examples of aryl groups include phenyl, naphthyl, fluorenyl, and anthryl. Aryl, however, does not encompass or overlap in any way with heteroaryl defined below. If one or more aryl groups are fused with a heteroaryl ring, the resulting ring system is heteroaryl.

“Cyano” or “carbonitrile” refers to the group —CN.

“Cycloalkyl” refers to a saturated or partially saturated cyclic alkyl group having a single ring or multiple rings including fused, bridged, and spiro ring systems. The term “cycloalkyl” includes cycloalkenyl groups (i.e. the cyclic group having at least one alkenyl). As used herein, cycloalkyl has from 3 to 20 ring carbon atoms (i.e., C₃₋₂₀ cycloalkyl), 3 to 12 ring carbon atoms (i.e., C₃₋₁₂ cycloalkyl), 3 to 10 ring carbon atoms (i.e., C₃₋₁₀ cycloalkyl), 3 to 8 ring carbon atoms (i.e., C₃₋₈ cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C₃₋₆ cycloalkyl). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

“Halogen” or “halo” includes fluoro, chloro, bromo, and iodo. “Haloalkyl” refers to an unbranched or branched alkyl group as defined above, wherein one or more hydrogen atoms are replaced by a halogen. For example, where a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkyl substituted with two (“di”) or three (“tri”) halo groups, which may be, but are not necessarily, the same halogen. Examples of haloalkyl include difluoromethyl (—CHF₂) and trifluoromethyl (—CF₃).

“Heteroalkyl” refers to an alkyl group in which one or more of the carbon atoms (and any associated hydrogen atoms) are each independently replaced with the same or different heteroatomic group. By way of example, 1, 2 or 3 carbon atoms may be independently replaced with the same or different heteroatomic group. Heteroatomic groups include, but are not limited to, —NR—, —O—, —S—, —S(O)—, —S(O)₂—, and the like, where R is H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl or heterocycloalkyl, each of which may be optionally substituted. Examples of heteroalkyl groups include —OCH₃, —CH₂OCH₃, —SCH₃, —CH₂SCH₃, —NRCH₃, and —CH₂NRCH₃, where R is hydrogen, alkyl, aryl, arylalkyl, heteroalkyl, or heteroaryl, each of which may be optionally substituted. As used herein, heteroalkyl include 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.

“Heteroaryl” refers to an aromatic group having a single ring, multiple rings, or multiple fused rings, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl include 1 to 20 ring carbon atoms (i.e., C₁₋₂₀ heteroaryl), 3 to 12 ring carbon atoms (i.e., C₃₋₁₂ heteroaryl), or 3 to 8 carbon ring atoms (i.e., C₃₋₈ heteroaryl); and 1 to 5 heteroatoms, 1 to 4 heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include pyrimidinyl, purinyl, pyridyl, pyridazinyl, benzothiazolyl, and pyrazolyl. Heteroaryl does not encompass or overlap with aryl as defined above.

“Heterocycloalkyl” refers to a saturated or unsaturated cyclic alkyl group, with one or more ring heteroatoms independently selected from nitrogen, oxygen and sulfur. The term “heterocycloalkyl” includes heterocycloalkenyl groups (i.e. the heterocycloalkyl group having at least one alkenyl). A heterocycloalkyl may be a single ring or multiple rings wherein the multiple rings may be fused, bridged, or spiro. As used herein, heterocycloalkyl has 2 to 20 ring carbon atoms (i.e., C₂₋₂₀ heterocycloalkyl), 2 to 12 ring carbon atoms (i.e., C₂₋₁₂ heterocycloalkyl), 2 to 10 ring carbon atoms (i.e., C₂₋₁₀ heterocycloalkyl), 2 to 8 ring carbon atoms (i.e., C₂₋₈ heterocycloalkyl), 3 to 12 ring carbon atoms (i.e., C₃₋₁₂ heterocycloalkyl), 3 to 8 ring carbon atoms (i.e., C₃₋₈ heterocycloalkyl), or 3 to 6 ring carbon atoms (i.e., C₃₋₆ heterocycloalkyl); having 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, sulfur or oxygen. Examples of heterocycloalkyl groups include pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, dioxolanyl, azetidinyl, and morpholinyl.

“Hydroxy” or “hydroxyl” refers to the group —OH.

“Oxo” refers to the group (═O) or (O).

“Sulfonyl” refers to the group —S(O)₂R, where R is alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, or aryl. Examples of sulfonyl are methylsulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.

Certain commonly used alternative chemical names may be used. For example, a divalent group such as a divalent “alkyl” group, a divalent “aryl” group, etc., may also be referred to as an “alkylene” group or an “alkylenyl” group, an “arylene” group or an “arylenyl” group, respectively. Also, unless indicated explicitly otherwise, where combinations of groups are referred to herein as one moiety, e.g. arylalkyl, the last mentioned group contains the atom by which the moiety is attached to the rest of the molecule.

The terms “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. Also, the term “optionally substituted” refers to any one or more hydrogen atoms on the designated atom or group may or may not be replaced by a moiety other than hydrogen.

The term “substituted” means that any one or more hydrogen atoms on the designated atom or group is replaced with one or more substituents other than hydrogen, provided that the designated atom's normal valence is not exceeded. The one or more substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo, haloalkyl, heteroalkyl, heteroaryl, heterocycloalkyl, hydroxy, hydrazino, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, thiol, thione, or combinations thereof. By way of example, there may be one, two, three, four, five, or six substituents. Polymers or similar indefinite structures arrived at by defining substituents with further substituents appended ad infinitum (e.g., a substituted aryl having a substituted alkyl which is itself substituted with a substituted aryl group, which is further substituted by a substituted heteroalkyl group, etc.) are not intended for inclusion herein. Unless otherwise noted, the maximum number of serial substitutions in compounds described herein is three. For example, serial substitutions of substituted aryl groups with two other substituted aryl groups are limited to substituted aryl (substituted aryl) substituted aryl. Similarly, the above definitions are not intended to include impermissible substitution patterns (e.g., methyl substituted with 5 fluorines or heteroaryl groups having two adjacent oxygen ring atoms). Such impermissible substitution patterns are well known to the skilled artisan. When used to modify a chemical group, the term “substituted” may describe other chemical groups defined herein. For example, the term “substituted aryl” includes, but is not limited to, “alkylaryl.” Unless specified otherwise, where a group is described as optionally substituted, any substituents of the group are themselves unsubstituted.

In some embodiments, the term “substituted alkyl” refers to an alkyl group having one or more substituents including hydroxyl, halo, alkoxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl. In additional embodiments, “substituted cycloalkyl” refers to a cycloalkyl group having one or more substituents including alkyl, haloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, halo, hydroxyl; “substituted aryl” refers to an aryl group having one or more substituents including halo, alkyl, haloalkyl, heterocycloalkyl, heteroaryl, alkoxy, and cyano, and “substituted sulfonyl” refers to a group —S(O)₂R, in which R is substituted with one or more substituents of alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl. In other embodiments, the one or more substituents may be further substituted with halo, alkyl, haloalkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is substituted. In other embodiments, the substituents may be further substituted with halo, alkyl, haloalkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is unsubstituted.

PI3K Inhibitor Compounds

The present application provides the compounds that function as inhibitors of PI3K isoforms. In one aspect, the PI3K inhibitors are the compounds having the structure of formula (J):

wherein:

W is CH or N;

X, Y and Z are independently selected from C(R′) or N, wherein at least one of X, Y, and Z is C(R′);

n is 0, 1, 2, 3, or 4;

m′ is 0 or 1; A′ is OR⁴, N(R⁵)C(O)R⁴, or NR⁵R⁴;

each R′ is independently selected from hydrogen, halo, optionally substituted alkyl, optionally substituted haloalkyl, and optionally substituted cycloalkyl;

each R¹ is independently selected from halo, cyano, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted alkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, and optionally substituted sulfonyl;

each R² is independently selected from halo, optionally substituted alkyl, optionally substituted haloalkyl, and optionally substituted cycloalkyl;

R³ is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted aryl;

R⁴ is heteroaryl optionally substituted with one, two, or three members independently selected from halo, cyano, —NH₂, optionally substituted alkyl, optionally substituted haloalkyl, and optionally substituted alkynyl; and

R⁵ is hydrogen or optionally substituted alkyl, wherein R⁵ and R³ together with the atoms to which they are attached optionally form a heterocyclic ring;

or a pharmaceutically acceptable salt, isomer, or a mixture thereof.

In certain embodiment, the compounds have the formula (J), wherein

W is CH or N;

X, Y and Z are independently selected from C(R′) or N, wherein at least one of X, Y, and Z is C(R′);

n is 0, 1, 2, 3, or 4;

m′ is 0 or 1; A′ is OR⁴, N(R⁵)C(O)R⁴, or NR⁵R⁴;

each R′ is independently selected from hydrogen, halo, —NH₂, optionally substituted alkyl, optionally substituted haloalkyl, and optionally substituted cycloalkyl;

each R¹ is independently selected from halo, cyano, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted alkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, and optionally substituted sulfonyl;

each R² is independently selected from halo, —NH₂, optionally substituted alkyl, optionally substituted haloalkyl, and optionally substituted cycloalkyl;

R³ is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted aryl;

R⁴ is heteroaryl optionally substituted with one, two, or three members independently selected from halo, cyano, —NH₂, optionally substituted alkyl, optionally substituted haloalkyl, and optionally substituted alkynyl; and

R⁵ is hydrogen or optionally substituted alkyl, wherein R⁵ and R³ together with the atoms to which they are attached optionally form a heterocyclic ring;

or a pharmaceutically acceptable salt, isomer, or a mixture thereof.

In an additional aspect, the PI3K inhibitors are the compounds having the structure of formula (I):

wherein:

X, Y and Z are independently selected from C(R′) or N, wherein at least one of X, Y, and Z is C(R′);

n is 0, 1, 2, 3, or 4;

m′ is 0 or 1;

A is a single bond or C(O);

each R′ is independently selected from hydrogen, halo, optionally substituted alkyl, optionally substituted haloalkyl, and optionally substituted cycloalkyl;

each R¹ is independently selected from halo, cyano, optionally substituted C₁₋₆ alkyl, optionally substituted C₁₋₆ alkoxy, hydroxy, optionally substituted C₃₋₈ cycloalkyl, and optionally substituted sulfonyl;

each R² is independently selected from halo, optionally substituted C₁₋₆ alkyl, optionally substituted C₁₋₆ haloalkyl, and optionally substituted C₃₋₈ cycloalkyl;

R³ is hydrogen, optionally substituted C₁₋₆ alkyl, optionally substituted C₃₋₈ cycloalkyl, or optionally substituted C₆₋₁₀ aryl;

R⁴ is a six- to twelve-membered heteroaryl having at least two heteroatoms, wherein each heteroatom is independently selected from N, O, or S, wherein the heteroaryl is optionally substituted with one, two, or three members independently selected from halo, cyano, —NH₂, optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkynyl; and

R⁵ is hydrogen or optionally substituted C₁₋₆ alkyl; R⁵ and R³ together with the atoms to which they are attached optionally form a four- to eight-membered heterocyclic ring;

or a pharmaceutically acceptable salt, isomer, or a mixture thereof.

The application further provides the compounds of formula (I), wherein

X, Y and Z are independently selected from C(R′) or N, wherein at least one of X, Y, and Z is N;

n is 1 or 2;

m′ is 0 or 1;

A is a single bond or C(O);

each R′ is independently selected from hydrogen, halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, or C₃₋₆ cycloalkyl, wherein the alkyl moiety is optionally substituted with C₁₋₄ alkoxy;

each R¹ is independently selected from halo, cyano, C₁₋₄ alkyl, C₁₋₄ haloalkyl, and —SO₂C₁₋₄ alkyl;

each R² is independently selected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, and C₃₋₆ cycloalkyl, wherein the alkyl moiety is optionally substituted with C₁₋₄ alkoxy;

R³ is hydrogen, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, or C₆₋₁₀ aryl; wherein the alkyl moiety is optionally substituted with hydroxyl or C₁₋₄ alkoxy, wherein C₁₋₄ alkoxy is optionally substituted with C₆₋₁₀ to aryl;

R⁴ is a six- to twelve-membered heteroaryl having at least one aromatic ring and at least two nitrogen atoms, wherein the heteroaryl is optionally substituted with 1 to 3 members independently selected from halo, cyano, —NH₂, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, and C₁₋₄ alkyl, wherein the C₂₋₄ alkynyl moiety is optionally substituted with C₆₋₁₀ aryl or C₃₋₈ heteroaryl, wherein each of the C₆₋₁₀ aryl and C₃₋₈ heteroaryl moieties is optionally substituted with halo or C₁₋₆ haloalkyl;

R⁵ is hydrogen or C₁₋₄ alkyl; R⁵ and R³ together with the nitrogen to which they are attached optionally form a five-membered heterocyclic ring;

or a pharmaceutically acceptable salt, isomer, or a mixture thereof.

In certain embodiment, the compounds have the structure of formula (I), wherein

X, Y and Z are independently selected from C(R′) or N, wherein at least one of X, Y, and Z is N;

n is 1 or 2;

m′ is 0 or 1;

A is a single bond or C(O);

each R′ is independently selected from hydrogen, halo, —NH₂, C₁₋₄ alkyl, C₁₋₄ haloalkyl, or C₃₋₆ cycloalkyl, wherein the alkyl moiety is optionally substituted with C₁₋₄ alkoxy;

each R¹ is independently selected from halo, cyano, C₁₋₄ alkyl, C₁₋₄ haloalkyl, and —SO₂C₁₋₄ alkyl;

each R² is independently selected from halo, —NH₂, C₁₋₄ alkyl, C₁₋₄ haloalkyl, and C₃₋₆ cycloalkyl, wherein the alkyl moiety is optionally substituted with C₁₋₄ alkoxy;

R³ is hydrogen, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, or C₆₋₁₀ aryl; wherein the alkyl moiety is optionally substituted with hydroxyl or C₁₋₄ alkoxy, wherein C₁₋₄ alkoxy is optionally substituted with C₆₋₁₀ aryl;

R⁴ is a six- to twelve-membered heteroaryl having at least one aromatic ring and at least two nitrogen atoms, wherein the heteroaryl is optionally substituted with 1 to 3 members independently selected from halo, cyano, —NH₂, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, and C₁₋₄ alkyl, wherein the C₂₋₄ alkynyl moiety is optionally substituted with C₆₋₁₀ aryl or C₃₋₈ heteroaryl, wherein each of the C₆₋₁₀ aryl and C₃₋₈ heteroaryl moieties is optionally substituted with halo or C₁₋₆ haloalkyl;

R⁵ is hydrogen or C₁₋₄ alkyl; R⁵ and R³ together with the nitrogen to which they are attached optionally form a five-membered heterocyclic ring;

or a pharmaceutically acceptable salt, isomer, or a mixture thereof.

In one embodiment, the compounds have the structure of formula (I), wherein

each R¹ is selected from fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, butyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, cyano, methylsulfonyl, and ethylsulfonyl;

each R² is selected from hydrogen, fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, butyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, methoxymethyl, methoxyethyl, ethoxymethyl, methoxypropyl, ethoxyethyl, ethoxypropyl, cyclopropyl, and cyclobutyl;

R³ is selected from methyl, ethyl, propyl, cyclopropyl, cyclobutyl, phenyl, benzyloxymethyl, benzyloxyethyl, benzyloxypropyl, —CH₂OH, —C₂H₄OH, or —C₃H₆OH;

R⁵ is selected from hydrogen, methyl, ethyl, or propyl; and

R⁴ is selected from purinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolopyrimidinyl, pyridopyrimidinyl, thienopyrimidinyl, pyrrolopyrimidinyl, furopyrimidinyl, or imidazotriazinyl; wherein each of the purinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolopyrimidinyl, pyridopyrimidinyl, thienopyrimidinyl, pyrrolopyrimidinyl, furopyrimidinyl, or imidazotriazinyl moieties is optionally substituted with 1 to 3 members selected from the group consisting of halo, cyano, —NH₂, C₁₋₄ alkyl, C₂₋₄ alkynyl, wherein the C₂₋₄ alkynyl moiety is optionally substituted with C₆₋₁₀ aryl or C₄₋₈ heteroaryl, wherein each of the C₆₋₁₀ aryl or C₃₋₈ heteroaryl moieties is optionally substituted with one, two, or three members selected from fluoro, chloro, bromo, iodo, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, and trifluoroethyl.

In one embodiment, the compounds have the structure of formula (I), wherein

each R¹ is selected from fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, butyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, cyano, methylsulfonyl, and ethylsulfonyl;

each R² is selected from hydrogen, fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, butyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, methoxymethyl, methoxyethyl, ethoxymethyl, methoxypropyl, ethoxyethyl, ethoxypropyl, cyclopropyl, cyclobutyl, and —NH₂;

R³ is selected from methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, phenyl, benzyloxymethyl, benzyloxyethyl, benzyloxypropyl, —CH₂OH, —C₂H₄OH, or —C₃H₆OH;

R⁵ is selected from hydrogen, methyl, ethyl, or propyl; and

R⁴ is selected from purinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolopyrimidinyl, pyridopyrimidinyl, thienopyrimidinyl, pyrrolopyrimidinyl, furopyrimidinyl, imidazotriazinyl, or pyrazolopyrimidinyl; wherein each of the purinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolopyrimidinyl, pyridopyrimidinyl, thienopyrimidinyl, pyrrolopyrimidinyl, furopyrimidinyl, imidazotriazinyl, or pyrazolopyrimidinyl moieties is optionally substituted with 1 to 3 members selected from the group consisting of halo, cyano, —NH₂, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₄ alkynyl, wherein the C₂₋₄ alkynyl moiety is optionally substituted with C₆₋₁₀ aryl or C₄₋₈ heteroaryl, wherein each of the C₆₋₁₀ aryl or C₃₋₈ heteroaryl moieties is optionally substituted with one, two, or three members selected from fluoro, chloro, bromo, iodo, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, and trifluoroethyl.

The application also provides that the compounds of formulae (J) or (I) having the structure of formula (Ia):

wherein n, A, R¹, R², R³, R⁴, and R⁵ are defined herein;

m is 0, 1, or 2;

or a pharmaceutically acceptable salt, isomer, or a mixture thereof.

Moreover, the compounds of formulae (J) or (I) may have the structure of formula (Ib)

wherein n, m, A, R¹, R², R³, R⁴, and R⁵ are defined herein;

or a pharmaceutically acceptable salt, isomer, or a mixture thereof.

In addition, the compounds of formulae (J) or (I) may have the structure of formula (II)

wherein n, m, A, R¹, R², R³, R⁴, and R⁵ are defined herein;

or a pharmaceutically acceptable salt, isomer, or a mixture thereof.

The application also provides that the compounds of formulae (J) or (I) having the structure of formula (IIa)

wherein n, m, R¹, R², R³, and R⁵ are defined herein;

p is 0, 1, 2, or 3;

each R^(4a) is independently selected from halo, cyano, NH₂, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, and C₁₋₄ alkyl, wherein the C₂₋₄ alkynyl moiety is optionally substituted with C₆₋₁₀ aryl or C₃₋₈ heteroaryl, wherein each of the C₆₋₁₀ aryl and C₃₋₈ heteroaryl moieties is optionally substituted with one, two, or three members independently selected from halo and C₁₋₆ haloalkyl;

or a pharmaceutically acceptable salt, isomer, or a mixture thereof.

The application also provides the compounds of formulae (J) or (I) having the structure of formula (IIb)

wherein n, m, p, R¹, R², R³, R^(4a), and R⁵ are defined herein;

or a pharmaceutically acceptable salt, isomer, or a mixture thereof.

Moreover, the compounds of formulae (J) or (I) may have the structure of formula (III):

wherein n, m, A, R¹, R², R³, R⁴, and R⁵ are defined herein;

or a pharmaceutically acceptable salt, isomer, or a mixture thereof.

The application also provides the compounds having the structure of formula (IIIa):

wherein n, m, p, R¹, R², R³, R^(4a), and R⁵ are defined herein;

or a pharmaceutically acceptable salt, isomer, or a mixture thereof.

The application also provides the compounds of formulae (J) or (I) having the structure of formula (IIIb)

wherein n, m, p, R¹, R², R³, R^(4a), and R⁵ are defined herein;

or a pharmaceutically acceptable salt, isomer, or a mixture thereof.

The application further provides the compounds of formulae (J) or (I) having the structure of formula (IV):

wherein n, m, A, R¹, R², R³, R⁴, and R⁵ are defined herein;

or a pharmaceutically acceptable salt, isomer, or a mixture thereof.

The compounds of formulae (J) or (I) may have the structure of formula (IVa):

wherein n, m, p, R¹, R², R³, R^(4a), and R⁵ are defined herein;

or a pharmaceutically acceptable salt, isomer, or a mixture thereof.

The compounds of formulae (J) or (I) may have the structure of formula (IVb)

wherein n, m, p, R¹, R², R³, R^(4a), and R⁵ are defined herein;

or a pharmaceutically acceptable salt, isomer, or a mixture thereof.

In other embodiments, the compounds have the structure of any of formulae (IIa), (IIb), (IIIa), (IIIb), (IVa), or (IVb), wherein each R^(4a) is independently selected from halo, cyano, —NH₂, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, and C₁₋₄ alkyl, wherein the C₂₋₄ alkynyl moiety is optionally substituted with C₆₋₁₀ aryl or C₃₋₈ heteroaryl, wherein each of the C₆₋₁₀ aryl and C₃₋₈ heteroaryl moieties is optionally substituted with one, two, or three members independently selected from halo, and C₁₋₆ haloalkyl. In some other embodiments, each R^(4a) is independently selected from bromo, fluoro, chloro, cyano, —NH₂, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, and C₂₋₄ alkynyl, wherein the C₂₋₄ alkynyl moiety is optionally substituted with C₆₋₁₀ aryl or C₄₋₈ heteroaryl, wherein each of the C₆₋₁₀ aryl or C₃₋₈ heteroaryl moieties is optionally substituted with one or two members independently selected from fluoro, chloro, bromo, iodo, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, and trifluoroethyl.

In any of the foregoing formulae (Ia), (Ib), (II), (III), and (IV), wherein n, R¹, R², R³, R⁴, and R⁵ are described herein; m is 0, 1, or 2; and A is a single bond or C(O). Moreover, in any of the foregoing formulae (IIa) (IIb), (IIIa), (IIIb), (IVa), and (IVb), wherein n, R¹, R², R³, and R⁵ are described herein; m is 0 or 1; p is 2 or 3; and each R^(4a) is independently selected from halo, cyano, C₂₋₄ alkynyl, C₃₋₄ haloalkyl, and C₁₋₄ alkyl, wherein the C₂₋₄ alkynyl moiety is optionally substituted with C₆₋₁₀ aryl or C₄₋₈ heteroaryl, wherein each of the C₆₋₁₀ aryl or C₃₋₈ heteroaryl moieties is optionally substituted with one or two members independently selected from fluoro, chloro, bromo, iodo, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, and trifluoroethyl.

In one embodiment, n is 0. In some embodiments, n is 1, 2, 3, or 4. In some embodiments, n is 1, 2, or 3. In other embodiments, n is 1 or 2. In certain embodiments, n is 1 and R¹ moiety may be located on any position of the phenyl of the quinazolinone ring. In another embodiment, n is 2. Both R¹ substituents or moieties may be the same or different. Two R¹ moieties may be located on any two positions of the phenyl of the quinazolinone ring. By way of example, the first R¹ may be ortho, meta, or para to the second R¹. In yet another embodiment, n is 3. All R¹ substituents or moieties may be the same or different, or two R¹ may be the same and different from the third R¹. Three R¹ moieties may be located on any three positions of the phenyl of the quinazolinone ring. For example, the first R¹ may be ortho to the second R¹, and the first R¹ may be para to the third R¹. In yet another embodiment, n is 4. All R¹ substituents may be the same or different, three R¹ may be the same and different from the fourth R¹, two R¹ may be the same and different from the third and the fourth R¹.

In some other embodiments, each R¹ is independently halo, cyano, optionally substituted C₁₋₆ alkyl, optionally substituted C₁₋₆ haloalkyl, optionally substituted C₁₋₆ alkoxy, hydroxy, optionally substituted C₃₋₆ cycloalkyl, optionally substituted C₃₋₆ heterocycloalkyl, optionally substituted C₆₋₁₀ aryl, optionally substituted C₄₋₈ heteroaryl, or optionally substituted C₁₋₆ alkylsulfonyl. In certain embodiments, each R¹ is independently halo, cyano, optionally substituted C₁₋₄ alkyl, optionally substituted C₁₋₄ haloalkyl, optionally substituted C₁₋₄ alkoxy, optionally substituted C₃₋₆ cycloalkyl, or optionally substituted C₁₋₄ alkylsulfonyl. In other embodiments, each R¹ is independently halo, cyano, C₁₋₄ haloalkyl, C₁₋₄ alkyl, or C₁₋₄ alkylsulfonyl. In certain embodiments, each R¹ is independently selected from fluoro, chloro, iodo, bromo, cyano, methyl, ethyl, propyl, butyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, methylsulfonyl, ethylsulfonyl, or propylsulfonyl. In some embodiments, each R¹ is independently fluoro, chloro, iodo, cyano, methyl, ethyl, difluoromethyl (—CHF₂), trifluoromethyl (—CF₃), methoxy, methylsulfonyl (—SO₂CH₃), cyclopropylmethyl, or cyclopropyl. In one embodiment, each R¹ is independently fluoro, chloro, cyano, methylsulfonyl, methyl, or trifluoromethyl.

In one embodiment, m is 0. In some embodiments, m is 1, 2, or 3. In certain other embodiment, m is 1 or 2. In yet other embodiment, m is 1 and R² substituent or moiety may be located on any position of the ring. In the embodiment where m is 2, both R² substituents may be the same or different. Two R² moieties may be located on any two positions of the ring. For example, the first R² may be ortho to the second R², and the first R² may be para to the third R². In embodiments where m is 3, all three R² may be the same or different, or two R² may be the same and different from the third R². Three R² moieties may be located on any three positions of the ring. It is understood that when two of X, Y, and Z are N, m may be 0, 1, or 2.

In one embodiment, m′ is 0. In some embodiments, m′ is 1 and R² may be located on the position of the carbon ring atom (e.g. not X, Y, or Z wherein one of X, Y, or Z is the attachment point to the quinazolinone ring) on the ring.

In certain embodiments, each R² is independently selected from halo, optionally substituted alkyl, optionally substituted haloalkyl, and optionally substituted cycloalkyl. In some embodiments, each R² is independently halo, C₁₋₄ haloalkyl, C₃₋₆ cycloalkyl, or C₁₋₄ alkyl optionally substituted with C₁₋₄ alkoxy. In some other embodiments, each R² is independently fluoro, chloro, iodo, bromo, —CH₂F, —CHF₂, —CF₃, fluoroethyl, difluoroethyl, trifluoroethyl, fluoropropyl, difluoropropyl, trifluoropropyl, methyl, ethyl, propyl, butyl, methoxymethyl, methoxyethyl, ethoxymethyl, methoxypropyl, ethoxyethyl, ethoxypropyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In one embodiment, each R² is independently fluoro, chloro, methyl, —CH₂F, —CHF₂, —CF₃, methoxyethyl, or cyclopropyl.

In certain embodiments, R³ is hydrogen, optionally substituted C₁₋₆ alkyl, optionally substituted C₃₋₈ cycloalkyl, or optionally substituted C₆₋₁₀ aryl. In one embodiment, R³ is hydrogen, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, or C₁₋₄ alkyl optionally substituted with hydroxy, C₆₋₁₀ arylC₁₋₄ alkoxy, or C₃₋₆ cycloalkyl. In some embodiments, R³ is hydrogen, methyl, ethyl, propyl, butyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, —CH₂OH, —C₂H₄OH, —C₃H₆OH, benzyloxymethyl

or phenyl

In additional embodiments, R⁵ is hydrogen or optionally substituted C₁₋₆ alkyl. In some embodiments, R⁵ is hydrogen or C₁₋₄ alkyl. In certain embodiments, R⁵ is hydrogen, methyl, ethyl, propyl or butyl. In certain other embodiments, R⁵ is hydrogen.

In further embodiments, R³ and R⁵ with the atoms to which they are attached (e.g. carbon and nitrogen, respectively) optionally form a heterocyclic ring. In other embodiments, the R³-R⁵ heterocyclic ring is a three- to eight-membered heterocycloalkyl (i.e. heterocycloalkyl having three to eight ring members and at least one ring member is a heteroatom). In other embodiments, the R³-R⁵ heterocyclic ring is a four- to seven-membered heterocycloalkyl (i.e. heterocycloalkyl having four to seven ring members and at least one ring member is a heteroatom). In other embodiment, the R³-R⁵ heterocyclic ring is optionally substituted with halo. In one embodiment, the R³-R⁵ heterocyclic ring is a five-membered heterocycloalkyl. In certain other embodiments, the R³-R⁵ heterocyclic ring is C₃₋₈ heterocycloalkyl. In certain embodiments, the R³-R⁵ heterocyclic ring is azepanyl, azetidinyl, piperidinyl, or pyrrolidinyl. In some other embodiments, the R³-R⁵ heterocyclic ring is pyrrolidinyl. In one other embodiment, the R³-R⁵ heterocyclic ring is a five-membered heterocycloalkyl substituted with halo. In other additional embodiments, the R³-R⁵ heterocyclic ring is pyrrolidinyl substituted with fluoro, chloro, bromo, or iodo.

In one embodiment, R⁴ is heteroaryl having at least two nitrogen atoms and at least one aromatic ring and R⁴ heteroaryl is optionally substituted one, two, or three members independently selected from halo, cyano, —NH₂, C₁₋₆ alkyl, and C₁₋₆ haloalkyl. In certain embodiments, R⁴ heteroaryl is a six- to twelve-membered heteroaryl (i.e. heteroaryl having six to twelve ring members). R⁴ heteroaryl may be a monocyclic or bicyclic heteroaryl. In some embodiments, R⁴ heteroaryl is a monocyclic heteroaryl having at least two nitrogen atoms. In certain embodiments, R⁴ heteroaryl is a bicyclic heteroaryl having at least one aromatic ring, at least two nitrogen atoms, and at least one additional heteroatom selected from N, O, or S. In certain other embodiments, R⁴ heteroaryl is selected from purinyl, pyrimidinyl, thiazolopyrimidinyl, pyridopyrimidinyl, thienopyrimidinyl, pyrrolopyrimidinyl, furopyrimidinyl, and imidazotriazinyl. In other embodiments, R⁴ heteroaryl is selected from purinyl, pyrimidinyl, thiazolopyrimidinyl, pyridopyrimidinyl, thienopyrimidinyl, pyrrolopyrimidinyl, furopyrimidinyl, imidazotriazinyl, and pyrazolopyrimidinyl. In some other embodiment, R⁴ heteroaryl is pyrazolopyrimidinyl.

In any of the foregoing formulae, R⁴ is heteroaryl optionally substituted with one, two, or three members independently selected from halo, cyano, —NH₂, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkynyl, wherein C₂₋₆ alkynyl is optionally substituted with C₆₋₁₀ aryl or C₄₋₈ heteroaryl, wherein each of the C₆₋₁₀ aryl or C₃₋₈ heteroaryl moieties is optionally substituted with one, two, or three members independently selected from fluoro, chloro, bromo, iodo, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, and trifluoroethyl, wherein the R⁴ heteroaryl is selected from the group consisting of

In additional embodiments, the R⁴ heteroaryl is selected from the group consisting of

In any of the foregoing formulae, R⁴ heteroaryl is optionally substituted with C₂₋₆ alkynyl optionally substituted with C₆₋₁₀ aryl or C₄₋₈ heteroaryl, each of which is optionally substituted with halo or C₁₋₆ haloalkyl. In some embodiment, R⁴ is heteroaryl optionally substituted with one member of C₂₋₆ alkynyl substituted with C₆₋₁₀ aryl or C₄₋₈ heteroaryl, wherein each of the C₆₋₁₀ aryl or C₃₋₈ heteroaryl moieties is optionally substituted with one member selected from fluoro, chloro, bromo, iodo, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, and trifluoroethyl. In some other embodiments, R⁴ heteroaryl is optionally substituted with one to three members independently selected from fluoro, chloro, bromo, iodo, cyano, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, —NH₂, and —C≡C optionally substituted with

In certain other embodiments, R⁴ is selected from purinyl, pyrimidinyl, thiazolopyrimidinyl, pyridopyrimidinyl, thienopyrimidinyl, pyrrolopyrimidinyl, furopyrimidinyl, and imidazotriazinyl, each of which is optionally substituted with one, two, or three members independently selected from chloro, fluoro, bromo, iodo, methyl, ethyl, propyl, cyano, and —NH₂. In certain other embodiments, R⁴ is selected from purinyl, pyrimidinyl, isothiazolopyrimidinyl, thiazolopyrimidinyl, pyridopyrimidinyl, thienopyrimidinyl, pyrrolopyrimidinyl, furopyrimidinyl, imidazotriazinyl, and pyrazolopyrimidinyl, each of which is optionally substituted with one, two, or three members independently selected from chloro, fluoro, bromo, iodo, methyl, ethyl, propyl, cyano, —NH₂, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, and trifluoroethyl. In certain other embodiments, R⁴ is selected from thiazolopyrimidinyl, pyridopyrimidinyl, thienopyrimidinyl, pyrrolopyrimidinyl, furopyrimidinyl, and imidazotriazinyl, each of which is optionally substituted with one or two members independently selected from chloro, fluoro, bromo, iodo, methyl, ethyl, propyl, and —NH₂. In other embodiments, R⁴ is selected from thiazolopyrimidinyl, pyridopyrimidinyl, thienopyrimidinyl, pyrrolopyrimidinyl, furopyrimidinyl, and imidazotriazinyl, each of which is optionally substituted with two members independently selected from chloro, fluoro, bromo, iodo, methyl, ethyl, propyl, and —NH₂. In other embodiments, R⁴ is selected from thiazolopyrimidinyl, pyridopyrimidinyl, thienopyrimidinyl, pyrrolopyrimidinyl, furopyrimidinyl, and imidazotriazinyl, each of which is optionally substituted with one member selected from chloro, fluoro, bromo, iodo, and —NH₂. In some other embodiments, R⁴ is pyrimidinyl or pyrazinyl and R⁴ is optionally substituted with at least one —NH₂. In certain other embodiments, R⁴ is pyrimidinyl or pyrazinyl, each substituted with two or three members independently selected from chloro, fluoro, bromo, iodo, methyl, ethyl, propyl, cyano, and —NH₂, and at least one of the two or three members is —NH₂. In other embodiments, R⁴ is pyrimidinyl or pyrazinyl, each substituted with two or three members independently selected from chloro, fluoro, bromo, iodo, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, cyano, and —NH₂, and at least one of the two or three members is —NH₂. In additional embodiments, R⁴ is isothiazolopyrimidinyl or pyrazolopyrimidinyl, each substituted with two or three members independently selected from chloro, fluoro, bromo, iodo, methyl, ethyl, propyl, cyano, —NH₂, fluoromethyl, difluoromethyl, and trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, and at least one of the two or three members is —NH₂.

In some embodiments, A is C(O). In certain embodiments, A is a single bond. Each and every variation of A may be combined with each and every variation of n, m′, m, X, Y, Z, R′, R¹, R², R³, R⁴, and R⁵ as described above. In some other embodiments, A is C(O) and R⁴ heteroaryl is a bicyclic group defined above. In other embodiments, A is a single bond and R⁴ heteroaryl is a bicyclic group defined above. In additional embodiments, A is C(O) and R⁴ heteroaryl is a monocyclic group selected from pyrimidinyl and pyrazinyl. In other embodiments, A is a single bond and R⁴ heteroaryl is a monocyclic group selected from pyrimidinyl and pyrazinyl.

In further embodiments, A′ is OR⁴. In some further embodiments, A′ is N(R⁵)C(O)R⁴. In yet further embodiments, A′ is NR⁵R⁴. Each and every variation of A′ may be combined with each and every variation of n, m′, X, Y, Z, R′, R¹, R², R³, R⁴, and R⁵ as described above.

In other embodiments, X, Y, and Z are independently C(R′) or N, wherein at least one of X, Y, and Z is C(R′). For example, in formulae (Ia) and (Ib) where X is C(R′), when Y is C(R′), Z is N or C(R′); when Y is N, Z is N or C(R′); when Z is C(R′), Y is N or C(R′); and when Z is N, Y is N or C(R′). In formula (I), X, Y, and Z are independently C(R′) or N, wherein at least one of X, Y, and Z is C(R′). In certain embodiments, all of X, Y, and Z are C(R′). In some embodiments, at least two of X, Y, and Z are C(R′). In other embodiments, at least one of X, Y, or Z is C(R′). In certain other embodiments, at least two of X, Y, and Z are N. In some other embodiments, at least one of X, Y, and Z is N. It is understood that R′ may be an attachment point to the quinazolinone ring. In such embodiments, X, Y, or Z is the attachment point to the quinazolinone ring by the R′ attachment. R′ is independently halo, optionally substituted alkyl, optionally substituted haloalkyl, and optionally substituted cycloalkyl. In some embodiments, each R′ is independently halo, C₁₋₄ alkyl which is optionally substituted with C₁₋₄ alkoxy, C₁₋₄ haloalkyl, or C₃₋₆ cycloalkyl. In some other embodiments, each R′ is independently fluoro, chloro, iodo, bromo, —CH₂F, —CHF₂, —CF₃, fluoroethyl, difluoroethyl, trifluoroethyl, fluoropropyl, difluoropropyl, trifluoropropyl, methyl, ethyl, propyl, butyl, methoxymethyl, methoxyethyl, ethoxymethyl, methoxypropyl, ethoxyethyl, ethoxypropyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In one embodiment, each R′ is independently fluoro, chloro, methyl, —CH₂F, —CHF₂, —CF₃, methoxyethyl, or cyclopropyl. In one embodiment, each R′ is independently —NH₂. In other embodiment, each R′ is independently halo, —NH₂, C₁₋₄ alkyl which is optionally substituted with C₁₋₄ alkoxy, C₁₋₄ haloalkyl, or C₃₋₆ cycloalkyl. In some other embodiment, each R′ is independently —NH₂, fluoro, chloro, methyl, —CH₂F, —CHF₂, —CF₃, methoxyethyl, or cyclopropyl.

In certain embodiments, W is CH or N. In certain other embodiments, W is CH. In yet other embodiments, W is N. Each and every variation of W may be combined with each and every variation of n, m′, X, Y, Z, A′, R′, R¹, R², and R³ as described above.

In the formulae (IIa), (IIb), (IIa), (IIIb), (IVa), and (IVb), n, R¹, R², R³, and R⁵ as described as formulae (I) and (J); m is 0, 1, or 2; p is 0, 1, 2, or 3; and R^(4a) is independently selected from halo, cyano, —NH₂, and optionally substituted C₁₋₆ alkyl.

In one embodiment, p is 0. In certain embodiments, p is 1, 2, or 3. In some embodiments, p is 1 or 2. In some embodiments, p is 1 and R^(4a) moiety may be located on any position of the pyrimidinyl or pyrazinyl ring. In another embodiment, p is 2 and both R^(4a) substituents or moieties may be the same or different; each of the two R^(4a) moiety may be located on any position of the pyrimidinyl or pyrazinyl ring. In yet another embodiment, p is 3 and all R^(4a) substituents may be the same or different, or two R^(4a) may be the same and different from the third R^(4a).

In the present application, each R^(4a) is independently selected from halo, —NH₂, cyano, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, and C₁₋₄ alkyl, wherein the C₂₋₄ alkynyl moiety is optionally substituted with C₆₋₁₀ aryl or C₄₋₈ heteroaryl, wherein each of the C₆₋₁₀ aryl or C₃₋₈ heteroaryl moieties is optionally substituted with one or two members independently selected from fluoro, chloro, bromo, iodo, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, and trifluoroethyl. In some embodiments, each R^(4a) is independently selected from fluoro, chloro, bromo, iodo, cyano, —NH₂, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, and difluoroethyl, wherein at least one R^(4a) is —NH₂. In additional embodiments, p is 2 or 3, and at least one R^(4a) is —NH₂. Each and every variation of p and R^(4a) may be combined with each and every variation of n, m, R¹, R², R³, and R⁵ as described above.

The compounds of the present application may bear one or more chiral centers. The compounds bearing the chiral center have the same molecular formula and the same chemical name with different stereoisomer designations. For example, the below 2,4-diamino-6-((1-(5-chloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile bearing one chiral center can be resolved into the (S) and (R) enantiomers, (S)-2,4-diamino-6-((1-(5-chloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile and ((R)-2,4-diamino-6-((1-(5-chloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile.

Representative compounds of the present application are listed in Table 1 below. Additional representative compounds are listed in Table 1a below. The compounds may be named using the nomenclature systems and symbols that are commonly recognized in the art of chemistry including, for example, ChemBioDraw Ultra 12.0, Chemical Abstract Service (CAS), and International Union of Pure and Applied Chemistry (IUPAC). For example, compound 1 in table 1 may be named as 2,4-diamino-6-[[(1S)-1-[5-chloro-4-oxo-3-(1H-pyrazol-3-yl)quinazolin-2-yl]propyl]amino]pyrimidine-5-carbonitrile or (S)-2,4-diamino-6-((1-(5-chloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile using IUPAC or ChemBioDraw Ultra 12.0, respectively.

TABLE 1 Representative Compounds Compound Structure 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

TABLE 1a Representative Compounds Compound Structure 127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

180

181

182

183

184

185

186

187

188

189

190

191

192

193

194

195

196

197

198

199

200

201

202

203

204

205

206

207

208

209

210

211

212

213

214

215

216

217

218

219

220

221

222

223

224

225

226

227

228

229

230

231

232

233

234

235

236

237

238

239

240

241

242

243

244

245

246

247

248

249

250

251

252

253

254

255

256

257

258

259

260

261

262

263

264

265

266

267

268

269

270

271

272

273

274

275

276

277

278

279

280

281

282

283

284

285

286

287

288

289

290

291

The present application provides pharmaceutically acceptable salts, hydrates, solvates, isomers, tautomers, stereoisomers, enantiomers, racemates, atropisomers, polymorphs, prodrugs, or a mixture thereof, of the compounds described herein. In addition, the present application provides the compounds in which from 1 to n hydrogen atoms attached to a carbon atom may be replaced by a deuterium atom or D, in which n is the number of hydrogen atoms in the molecule. It is known that the deuterium atom is a non-radioactive isotope of the hydrogen atom. Such compounds may increase resistance to metabolism, and thus may be useful for increasing the half-life of the compounds of any of the formulae described herein or pharmaceutically acceptable salts, isomers, prodrugs, or solvates thereof, when administered to a mammal. See, e.g., Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism”, Trends Pharmacol. Sci., 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogen atoms have been replaced by deuterium.

The terms “a compound of the present application,” “a compound described herein,” “a compound of any of the formulae described herein,” or variant thereof refer to a compound having the structure of any of the formulae (J), (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), and (IVb). In some embodiments, compounds of the present application are Compounds 1-291 as described herein.

“Pharmaceutically acceptable” or “physiologically acceptable” refer to compounds, salts, compositions, dosage forms and other materials which are useful in preparing a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use. “Pharmaceutically acceptable salts” or “physiologically acceptable salts” refer to salts of pharmaceutical compounds that retain the biological effectiveness and properties of the underlying compound, and which are not biologically or otherwise undesirable. There are acid addition salts and base addition salts. Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids. Acids and bases useful for reaction with an underlying compound to form pharmaceutically acceptable salts (acid addition or base addition salts respectively) are known to one of skill in the art. Similarly, methods of preparing pharmaceutically acceptable salts from an underlying compound (upon disclosure) are known to one of skill in the art and are disclosed in for example, Berge, at al. Journal of Pharmaceutical Science, January 1977 vol. 66, No. 1, and other sources. If the compounds described herein are obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds.

“Isomers” refers to compounds that have the same molecular formula. As used herein, the term isomers include double bond isomers, racemates, stereoisomers, enantiomers, diastereomers, and atropisomers. Single isomers, such as enantiomers or diastereomers, can be obtained by asymmetric synthesis or by resolution of a mixture of isomers. Resolution of a mixture of isomers (e.g. racemates) maybe accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example a chiral high pressure liquid chromatography (HPLC) column. “Double bond isomers” refer to Z- and E-forms (or cis- and trans-forms) of the compounds with carbon-carbon double bonds.

“Atropisomers” refers to conformational stereoisomers which occur when rotation about a single bond in the molecule is prevented, or greatly hindered, as a result of steric interactions with other parts of the molecule and the substituents at both ends of the single bond are asymmetrical, i.e., they do not require a stereocenter. Where the rotational barrier about the single bond is high enough, and interconversion between conformations is slow enough, separation and isolation of the isomeric species may be permitted. Atropisomers may be separated by the methods well known in the art. Unless otherwise indicated, the description is intended to include individual atropisomers as well as mixtures. Also, as understood by those skilled in the art, the atropisomers may be represented by the same chemical name with different atropisomer designations. By way of example, the below structures are atropisomers of compound 84, (S)-2,4-diamino-6-((1-(3-(4-bromo-1H-pyrazol-3-yl)-5-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile.

“Racemates” refers to a mixture of enantiomers.

“Stereoisomers” or “stereoisomeric forms” refer to compounds that differ in the chirality of one or more stereocenters. Stereoisomers include enantiomers and diastereomers. The compounds may exist in stereoisomeric form if they possess one or more asymmetric centers or a double bond with asymmetric substitution and, therefore, can be produced as individual stereoisomers or as mixtures. Unless otherwise indicated, the description is intended to include individual stereoisomers as well as mixtures. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see. e.g., Chapter 4 of Advanced Organic Chemistry, 4th ed., J. March, John Wiley and Sons, New York, 1992).

“Tautomers” or “tautomeric formers” refer to alternate forms of a compound that differ in the position of a proton, such as enol-keto and imine-enamine tautomers, or heteroaryls such as pyrazoles, imidazoles, benzimidazoles, triazoles, and tetrazoles.

A “solvate” is formed by the interaction of a solvent and a compound. Solvates of salts of the compounds of any of the formulae described herein are also provided. Hydrates of the compounds of any of the formulae are also provided.

A “prodrug” is defined in the pharmaceutical field as a biologically inactive derivative of a drug that upon administration to the human body is converted to the biologically active parent drug according to some chemical or enzymatic pathway.

In any one of the foregoing embodiments, the compound described herein or a pharmaceutically acceptable salt thereof is an (S)-enantiomer. In any one of the foregoing embodiments, the compound described herein or a pharmaceutically acceptable salt thereof is an (R)-enantiomer. In any one of the foregoing embodiments, the compound described herein or a pharmaceutically acceptable salt thereof is an atropisomer.

The application also provides a composition containing a mixture of enantiomers of the compound or a pharmaceutically acceptable salt thereof. In one embodiment, the mixture is a racemic mixture. In other embodiments, the composition comprises the (S)-enantiomer of a compound in excess of over the corresponding the (R)-enantiomer of the compound. In some embodiments, the composition contains the (S)-enantiomer of the compound and is substantially free of its corresponding (R)-enantiomer. In certain embodiments, a composition substantially free of the (R)-enantiomer has less than or about 40%, 35%, 30%, 25%, 20%, 15%, 10%, 5%, 1%, 0.05%, or 0.01% of the (R)-enantiomer. In other embodiments, the composition containing the (S)-enantiomer of a compound or a pharmaceutically acceptable salt thereof, predominates over its corresponding (R)-enantiomer by a molar ratio of at least or about 9:1, at least or about 19:1, at least or about 40:1, at least or about 80:1, at least or about 160:1, or at least or about 320:1.

The composition containing a compound according to any of the formulae described herein or a pharmaceutically acceptable salt thereof, may also contain the compound in enantiomeric excess (e.e.). By way of example, a compound with 95% (S)-isomer and 5% (R)-isomer will have an e.e. of 90%. In some embodiments, the compound has an e.e. of at least or about 60%, 75%, 80%, 85%, 90%, 95%, 98% or 99%.

In any one of the foregoing embodiments, the compound or a pharmaceutically acceptable salt thereof, is an atropisomer. Another embodiment provides the composition containing a mixture of atropisomers of the compound or a pharmaceutically acceptable salt thereof. By way of example, a compound with 95% of one atropisomer and 5% of the other atropisomers. In some embodiments, a compound with about 90, 80, 70, 60, 50, 40, 30, 20, or 10% of one atropisomer and 10, 20, 30, 40, 50, 60, 70, 80, or 90%, respectively, of the other atropisomers.

The application also provides the free base forms of the compounds described herein. In certain embodiments, provided herein are the enantiomers, (R) or (S), of the compounds of the formulae described herein. In other embodiments, provided herein are the atropisomers of the compounds of the formulae described herein.

The application further provides compositions comprising the compounds described herein or a pharmaceutically acceptable salt, isomer, prodrug, or solvate thereof. The composition may include racemic mixtures, mixtures containing an enantiomeric excess of one enantiomer or single diastereomers or diastereomeric mixtures. All such isomeric forms of these compounds are expressly included herein, the same as if each and every isomeric form were specifically and individually listed.

In certain embodiments, provided herein are also polymorphs, such as crystalline and amorphous forms, of the compounds described herein. In some embodiments, provided are also chelates, non-covalent complexes, and mixtures thereof, of the compounds of the formula described herein or pharmaceutically acceptable salts, prodrugs, or solvates thereof. A “chelate” is formed by the coordination of a compound to a metal ion at two (or more) points. A “non-covalent complex” is formed by the interaction of a compound and another molecule wherein a covalent bond is not formed between the compound and the molecule. For example, complexation can occur through van der Waals interactions, hydrogen bonding, and electrostatic interactions (also called ionic bonding).

Therapeutic Uses of the Compounds

The compounds of the formulae described herein or a pharmaceutically acceptable salt, isomer, prodrug, or solvate thereof may be used for the treatment of diseases and/or conditions mediated by PI3K isoforms. In addition, the application provides the compounds for use in therapy. Also, provided herein are methods for inhibiting one or more PI3K isoforms. In one embodiment, provided are methods for inhibiting PI3Kδ activity using the compound described herein or a pharmaceutically acceptable salt, isomer, prodrug, or solvate thereof. In other embodiment, provided are methods for inhibiting PI3Kδ and/or PI3Kβ activities using the compound or a pharmaceutically acceptable salt, isomer, prodrug, or solvate thereof. The application further provides methods for use in such methods. The PI3K isoforms may be selectively or specifically inhibited. Additionally, the compounds may be used to inhibit PI3K activity therapeutically or prophylactically, such as PI3Kδ and/or PI3Kβ.

The compounds according to the present application may be used in combination with one or more additional therapeutic agents. The therapeutic agents may be in the forms of compounds, antibodies, polypeptides, or polynucleotides. The therapeutic agent includes, but is not limited to, a chemotherapeutic agent, an immunotherapeutic agent, a radiotherapeutic agent, an anti-neoplastic agent, an anti-cancer agent, an anti-proliferation agent, an anti-fibrotic agent, an anti-angiogenic agent, a therapeutic antibody, or any combination thereof. In one embodiment, the application provides a product comprising a compound described herein and an additional therapeutic agent as a combined preparation for simultaneous, separate or sequential use in therapy, e.g. a method of treating a disease, disorder, or condition that is mediated by PI3K isoforms.

Also, the therapeutic agents may be those that inhibit or modulate the activities of Bruton's tyrosine kinase, spleen tyrosine kinase, apoptosis signal-regulating kinase, Janus kinase, lysyl oxidase, lysyl oxidase-like proteins, matrix metallopeptidase, bromodomain-containing protein, adenosine A2B receptor, isocitrate dehydrogenase, serine/threonine kinase TPL2, discoidin domain receptor, serine/threonine-protein kinases, IKK, MEK, EGFR, histone deacetylase, protein kinase C, or any combination thereof. In certain embodiments, the therapeutic agent may be selected from a PI3K (including PI3Kγ, PI3Kδ, PI3Kβ, PI3Kα, and/or pan-PI3K) inhibitor, a JAK (Janus kinase, including JAK1, JAK2, and/or JAK3) inhibitor, a SYK (spleen tyrosine kinase) inhibitor, a BTK (Bruton's tyrosine kinase) inhibitor, an A2B (adenosine A2B receptor) inhibitor, an ACK (activated CDC kinase, including ACK1) inhibitor, an ASK (apoptosis signal-regulating kinase, including ASK1) inhibitor, Aurora kinase, a BRD (bromodomain-containing protein, including BRD4) inhibitor, a Bcl (B-cell CLL/lymphoma, including Bcl-1 and/or Bcl-2) inhibitor, a CAK (CDK-activating kinase) inhibitor, a CaMK (calmodulin-dependent protein kinases) inhibitor, a CDK (cyclin-dependent kinases, including CDK1, 2, 3, 4, and/or 6) inhibitor, a CK (casein kinase, including CK1 and/or CK2) inhibitor, a DDR (discoidin domain receptor, including DDR1 and/or DDR2) inhibitor, a EGFR inhibitor, a FXR (farnesoid×receptor) inhibitor, a FAK (focal adhesion kinase) inhibitor, a GSK (glycogen synthase kinase) inhibitor, a HDAC (histone deacetylase) inhibitor, an IDO (indoleamine 2,3-dioxygenase) inhibitor, an IDH (isocitrate dehydrogenase, including IDH1) inhibitor, an IKK (1-Kappa-B kinase) inhibitor, a KDM5 (lysine demethylase) inhibitor, a LCK (lymphocyte-specific protein tyrosine kinase) inhibitor, a LOX (lysyl oxidase) inhibitor, a LOXL (lysyl oxidase like protein, including LOXL1, LOXL2, LOXL3, LOXL4, and/or LOXL5) inhibitor, a MTH (mut T homolog) inhibitor, a MEK (mitogen-activated protein kinase kinase) inhibitor, a matrix metalloprotease (MMP, including MMP2 and/or MMP9) inhibitor, a mitogen-activated protein kinases (MAPK) inhibitor, a PD-1 (programmed cell death protein 1) inhibitor, a PD-L1 (programmed death-ligand 1) inhibitor, a PDGF (platelet-derived growth factor) inhibitor, a phosphorylase kinase (PK) inhibitor, a PLK (polo-like kinase, including PLK1, 2, 3) inhibitor, a protein kinase (PK, including protein kinase A, B, C) inhibitor, a STK (serine/threonine kinase) inhibitor, a STAT (signal transduction and transcription) inhibitor, a serine/threonine-protein kinase inhibitor, a TBK (tank-binding kinase) inhibitor, a TLR (toll-like receptor modulators, including TLR-1, TLR-2, TLR-3, TLR-4, TLR-5, TLR-6, TLR-7, TLR-8, TLR-9, TLR-10, TLR-11, TLR-12, and/or TLR-13) inhibitor, a TK (tyrosine kinase) inhibitor, a TPL2 (serine/threonine kinase) inhibitor, a NEK9 inhibitor, an Abl inhibitor, a p38 kinase inhibitor, a PYK inhibitor, a PYK inhibitor, a c-Kit inhibitor, a NPM-ALK inhibitor, a Fit-3 inhibitor, a c-Met inhibitor, a KDR inhibitor, a TIE-2 inhibitor, a VEGFR inhibitor, a SRC inhibitor, a HCK inhibitor, a LYN inhibitor, a FYN inhibitor, a YES inhibitor, a chemotherapeutic agent, an immunotherapeutic agent, a radiotherapeutic agent, an anti-neoplastic agent, an anti-cancer agent, an anti-proliferation agent, an anti-fibrotic agent, an anti-angiogenic agent, a therapeutic antibody, or any combination thereof. In some embodiments, the JAK inhibitor is N-(cyanomethyl)-4-[2-(4-morpholinoanilino)pyrimidin-4-yl]benzamide as named by ChemDraw (may also be referred to as CYT0387 or momelotinib) and may be synthesized by the methods described in U.S. Pat. No. 8,486,941. In certain embodiment, the SyK inhibitor is 6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo[1,2-a]pyrazin-8-amine as named by ChemDraw (may also be referred to as 6-(1H-indazol-6-yl)-N-[4-(morpholin-4-yl)phenyl]imidazo[1,2-a]pyrazin-8-amine) and may be synthesized by the methods described in U.S. Pat. No. 8,450,321. In other embodiments, the BTK inhibitor is (S)-6-amino-9-(1-(but-2-ynoyl)pyrrolidin-3-yl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one as named by ChemDraw (may also be 6-amino-9-[(3R)-1-(2-butynoyl)-3-pyrrolidinyl]-7-(4-phenoxyphenyl)-7,9-dihydro-8H-purin-8-one) and may be synthesized by the methods in U.S. Pat. No. 8,557,803.

Chemotherapeutic agents may be categorized by their mechanism of action into, for example, the following groups: anti-metabolites/anti-cancer agents, such as pyrimidine analogs (floxuridine, capecitabine, and cytarabine); purine analogs, folate antagonists and related inhibitors, antiproliferative/antimitotic agents including natural products such as vinca alkaloid (vinblastine, vincristine) and microtubule such as taxane (paclitaxel, docetaxel), vinblastin, nocodazole, epothilones and navelbine, epidipodophyllotoxins (etoposide, teniposide); DNA damaging agents (actinomycin, amsacrine, busulfan, carboplatin, chlorambucil, cisplatin, cyclophosphamide, Cytoxan, dactinomycin, daunorubicin, doxorubicin, epirubicin, iphosphamide, melphalan, merchlorehtamine, mitomycin, mitoxantrone, nitrosourea, procarbazine, taxol, taxotere, teniposide, etoposide, triethylenethiophosphoramide); antibiotics such as dactinomycin (actinomycin D), daunorubicin, doxorubicin (adriamycin), idarubicin, anthracyclines, mitoxantrone, bleomycins, plicamycin (mithramycin) and mitomycin; enzymes (L-asparaginase which systemically metabolizes L-asparagine and deprives cells which do not have the capacity to synthesize their own asparagine); antiplatelet agents; antiproliferative/antimitotic alkylating agents such as nitrogen mustards cyclophosphamide and analogs, melphalan, chlorambucil), and (hexamethylmelamine and thiotepa), alkyl nitrosoureas (BCNU) and analogs, streptozocin), trazenes-dacarbazinine (DTIC); antiproliferative/antimitotic antimetabolites such as folic acid analogs (methotrexate); platinum coordination complexes (cisplatin, oxiloplatinim, carboplatin), procarbazine, hydroxyurea, mitotane, aminoglutethimide; hormones, hormone analogs (estrogen, tamoxifen, goserelin, bicalutamide, nilutamide) and aromatase inhibitors (letrozole, anastrozole); anticoagulants (heparin, synthetic heparin salts and other inhibitors of thrombin); fibrinolytic agents (such as tissue plasminogen activator, streptokinase and urokinase), aspirin, dipyridamole, ticlopidine, clopidogrel; antimigratory agents; antisecretory agents (breveldin); immunosuppressives tacrolimus sirolimus azathioprine, mycophenolate; compounds (TNP-470, genistein) and growth factor inhibitors (vascular endothelial growth factor inhibitors, fibroblast growth factor inhibitors); angiotensin receptor blocker, nitric oxide donors; anti-sense oligonucleotides; antibodies (trastuzumab, rituximab); cell cycle inhibitors and differentiation inducers (tretinoin); inhibitors, topoisomerase inhibitors (doxorubicin (adriamycin), daunorubicin, dactinomycin, eniposide, epirubicin, etoposide, idarubicin, irinotecan and mitoxantrone, topotecan, irinotecan, camptothesin), corticosteroids (cortisone, dexamethasone, hydrocortisone, methylpednisolone, prednisone, and prenisolone); growth factor signal transduction kinase inhibitors; dysfunction inducers, toxins such as Cholera toxin, ricin, Pseudomonas exotoxin, Bordetella pertussis adenylate cyclase toxin, or diphtheria toxin, and caspase activators; and chromatin.

As used herein the term “chemotherapeutic agent” or “chemotherapeutic” (or “chemotherapy,” in the case of treatment with a chemotherapeutic agent) is meant to encompass any non-proteinaceous (i.e, non-peptidic) chemical compound useful in the treatment of cancer. Examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide (CYTOXAN); alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; emylerumines and memylamelamines including alfretamine, triemylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimemylolomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including synthetic analogue topotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizclesin synthetic analogues); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogues, KW-2189 and CBI-TMI); eleutherobin; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmustine, chlorozotocin, foremustine, lomustine, nimustine, ranimustine; antibiotics such as the enediyne antibiotics (e.g., calicheamicin, especially calicheamicin gammaI1 and calicheamicin phil1, see, e.g., Agnew, Chem. Intl. Ed. Engl, 33:183-186 (1994); dynemicin, including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromomophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, carminomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin (including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogues such as demopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogues such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replinisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; hestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elformthine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; leucovorin; lonidamine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; losoxantrone; fluoropyrimidine; folinic acid; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK®; razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2′,2″-tricUorotriemylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A and anguidine); urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (“Ara-C”); cyclophosphamide; thiopeta; taxoids, e.g., paclitaxel (TAXOL® and docetaxel (TAXOTERE®); chlorambucil; gemcitabine (Gemzar®); 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitroxantrone; vancristine; vinorelbine (Navelbine®); novantrone; teniposide; edatrexate; daunomycin; aminopterin; xeoloda; ibandronate; CPT-11; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; capecitabine; FOLFIRI (fluorouracil, leucovorin, and irinotecan) and pharmaceutically acceptable salts, acids or derivatives of any of the above. One or more chemotherapeutic agent are used or included in the present application.

Also included in the definition of “chemotherapeutic agent” are anti-hormonal agents that act to regulate or inhibit hormone action on tumors such as anti-estrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including Nolvadex™), raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LYI 17018, onapristone, and toremifene (Fareston®); inhibitors of the enzyme aromatase, which regulates estrogen production in the adrenal glands, such as, for example, 4(5)-imidazoles, aminoglutethimide, megestrol acetate (Megace®), exemestane, formestane, fadrozole, vorozole (Rivisor®), letrozole (Femara®), and anastrozole (Arimidex®.); and anti-androgens such as flutamide, nilutamide, bicalutamide, leuprohde, and goserelin; and pharmaceutically acceptable salts, acids or derivatives of any of the above.

The anti-angiogenic agents include, but are not limited to, retinoid acid and derivatives thereof, 2-methoxyestradiol, ANGIOSTATIN®, ENDOSTATIN®, suramin, squalamine, tissue inhibitor of metalloproteinase-1, tissue inhibitor of metalloproternase-2, plasminogen activator inhibitor-1, plasminogen activator inhibitor-2, cartilage-derived inhibitor, paclitaxel (nab-paclitaxel), platelet factor 4, protamine sulphate (clupeine), sulphated chitin derivatives (prepared from queen crab shells), sulphated polysaccharide peptidoglycan complex (sp-pg), staurosporine, modulators of matrix metabolism, including for example, proline analogs ((1-azetidine-2-carboxylic acid (LACA), cishydroxyproline, d,l-3,4-dehydroproline, thiaproline, .alpha.-dipyridyl, beta-aminopropionitrile fumarate, 4-propyl-5-(4-pyridinyl)-2(3h)-oxazolone; methotrexate, mitoxantrone, heparin, interferons, 2 macroglobulin-serum, chimp-3, chymostatin, beta-cyclodextrin tetradecasulfate, eponemycin; fumagillin, gold sodium thiomalate, d-penicillamine (CDPT), beta-1-anticollagenase-serum, alpha-2-antiplasmin, bisantrene, lobenzarit disodium, n-2-carboxyphenyl-4-chloroanthronilic acid disodium or “CCA”, thalidomide; angiostatic steroid, carboxynaminolmidazole; metalloproteinase inhibitors such as BB94. Other anti-angiogenesis agents include antibodies, preferably monoclonal antibodies against these angiogenic growth factors: beta-FGF, alpha-FGF, FGF-5, VEGF isoforms, VEGF-C, HGF/SF and Ang-1/Ang-2. See Ferrara N. and Alitalo, K. “Clinical application of angiogenic growth factors and their inhibitors” (1999) Nature Medicine 5:1359-1364.

The anti-fibrotic agents include, but are not limited to, the compounds such as beta-aminopropionitrile (BAPN), as well as the compounds disclosed in U.S. Pat. No. 4,965,288 to Palfreyman, et al., issued Oct. 23, 1990, entitled “Inhibitors of lysyl oxidase,” relating to inhibitors of lysyl oxidase and their use in the treatment of diseases and conditions associated with the abnormal deposition of collagen; U.S. Pat. No. 4,997,854 to Kagan, et al., issued Mar. 5, 1991, entitled “Anti-fibrotic agents and methods for inhibiting the activity of lysyl oxidase in situ using adjacently positioned diamine analogue substrate,” relating to compounds which inhibit LOX for the treatment of various pathological fibrotic states, which are herein incorporated by reference. Further exemplary inhibitors are described in U.S. Pat. No. 4,943,593 to Palfreyman, et al., issued Jul. 24, 1990, entitled “Inhibitors of lysyl oxidase,” relating to compounds such as 2-isobutyl-3-fluoro-, chloro-, or bromo-allylamine; as well as, e.g., U.S. Pat. No. 5,021,456; U.S. Pat. No. 5,5059,714; U.S. Pat. No. 5,120,764; U.S. Pat. No. 5,182,297; U.S. Pat. No. 5,252,608 (relating to 2-(1-naphthyloxymemyl)-3-fluoroallylamine); and U.S. Patent Application No. 2004/0248871, which are herein incorporated by reference. Exemplary anti-fibrotic agents also include the primary amines reacting with the carbonyl group of the active site of the lysyl oxidases, and more particularly those which produce, after binding with the carbonyl, a product stabilized by resonance, such as the following primary amines: emylenemamine, hydrazine, phenylhydrazine, and their derivatives, semicarbazide, and urea derivatives, aminonitriles, such as beta-aminopropionitrile (BAPN), or 2-nitroethylamine, unsaturated or saturated haloamines, such as 2-bromo-ethylamine, 2-chloroethylamine, 2-trifluoroethylamine, 3-bromopropylamine, p-halobenzylamines, selenohomocysteine lactone. Also, the anti-fibrotic agents are copper chelating agents, penetrating or not penetrating the cells. Exemplary compounds include indirect inhibitors such compounds blocking the aldehyde derivatives originating from the oxidative deamination of the lysyl and hydroxylysyl residues by the lysyl oxidases, such as the thiolamines, in particular D-penicillamine, or its analogues such as 2-amino-5-mercapto-5-methylhexanoic acid, D-2-amino-3-methyl-3-((2-acetamidoethyl)dithio)butanoic acid, p-2-amino-3-methyl-3-((2-aminoethyl)dithio)butanoic acid, sodium-4-((p-1-dimethyl-2-amino-2-carboxyethyl)dithio)butane sulphurate, 2-acetamidoethyl-2-acetamidoethanethiol sulphanate, sodium-4-mercaptobutanesulphinate trihydrate.

The immunotherapeutic agents include and are not limited to therapeutic antibodies suitable for treating patients; such as abagovomab, adecatumumab, afutuzumab, alemtuzumab, altumomab, amatuximab, anatumomab, arcitumomab, bavituximab, bectumomab, bevacizumab, bivatuzumab, blinatumomab, brentuximab, cantuzumab, catumaxomab, cetuximab, citatuzumab, cixutumumab, clivatuzumab, conatumumab, daratumumab, drozitumab, duligotumab, dusigitumab, detumomab, dacetuzumab, dalotuzumab, ecromeximab, elotuzumab, ensituximab, ertumaxomab, etaracizumab, farictuzumab, ficlatuzumab, figitumumab, flanvotumab, futuximab, ganitumab, gemtuzumab, girentuximab, glembatumumab, ibritumomab, igovomab, imgatuzumab, indatuximab, inotuzumab, intetumumab, ipilimumab, iratumumab, labetuzumab, lexatumumab, lintuzumab, lorvotuzumab, lucatumumab, mapatumumab, matuzumab, milatuzumab, minretumomab, mitumomab, moxetumomab, narnatumab, naptumomab, necitumumab, nimotuzumab, nofetumomabn, ocaratuzumab, ofatumumab, olaratumab, onartuzumab, oportuzumab, oregovomab, panitumumab, parsatuzumab, patritumab, pemtumomab, pertuzumab, pintumomab, pritumumab, racotumomab, radretumab, rilotumumab, rituximab, robatumumab, satumomab, sibrotuzumab, siltuximab, simtuzumab, solitomab, tacatuzumab, taplitumnomab, tenatumomab, teprotumumab, tigatuzumab, tositumomab, trastuzumab, tucotuzumab, ublituximab, veltuzumab, vorsetuzumab, votumumab, zalutumumab, obinutuzumab, CC49 and 3F8. The exemplified therapeutic antibodies may be further labeled or combined with a radioisotope particle, such as indium In 111, yttrium Y 90, iodine I-131.

The application also provides method for treating a subject who is undergoing one or more standard therapies, such as chemotherapy, radiotherapy, immunotherapy, surgery, or combination thereof. Accordingly, one or more therapeutic agent or inhibitors may be administered before, during, or after administration of chemotherapy, radiotherapy, immunotherapy, surgery or combination thereof.

Other examples of chemotherapy treatments (including standard or experimental chemotherapies) are described below. In addition, treatment of certain lymphomas is reviewed in Cheson, B. D., Leonard, J. P., “Monoclonal Antibody Therapy for B-Cell Non-Hodgkin's Lymphoma” The New England Journal of Medicine 2008, 359(6), p. 613-626; and Wierda, W. G., “Current and Investigational Therapies for Patients with CLL” Hematology 2006, p. 285-294. Lymphoma incidence patterns in the United States is profiled in Morton, L. M., et al. “Lymphoma Incidence Patterns by WHO Subtype in the United States, 1992-2001” Blood 2006, 107(1), p. 265-276.

Examples of immunotherapeutic agents include, but are not limited to, rituximab (such as Rituxan), alemtuzumab (such as Campath, MabCampath), anti-CD19 antibodies, anti-CD20 antibodies, anti-MN-14 antibodies, anti-TRAIL, Anti-TRAIL DR4 and DR5 antibodies, anti-CD74 antibodies, apolizumab, bevacizumab, CHIR-12.12, epratuzumab (hLL2-anti-CD22 humanized antibody), galiximab, ha20, ibritumomab tiuxetan, lumiliximab, milatuzumab, ofatumumab, PRO131921, SGN-40, WT-1 analog peptide vaccine, WT1 126-134 peptide vaccine, tositumomab, autologous human tumor-derived HSPPC-96, and veltuzumab. Additional immunotherapy agents includes using cancer vaccines based upon the genetic makeup of an individual patient's tumor, such as lymphoma vaccine example is GTOP-99 (MyVax®).

Examples of chemotherapy agents include aldesleukin, alvocidib, antineoplaston AS2-1, antineoplaston A10, anti-thymocyte globulin, amifostine trihydrate, aminocamptothecin, arsenic trioxide, beta alethine, Bcl-2 family protein inhibitor ABT-263, ABT-199, BMS-345541, bortezomib (Velcade®), bryostatin 1, busulfan, carboplatin, campath-1H, CC-5103, carmustine, caspofungin acetate, clofarabine, cisplatin, Cladribine (Leustarin), Chlorambucil (Leukeran), Curcumin, cyclosporine, Cyclophosphamide (Cyloxan, Endoxan, Endoxana, Cyclostin), cytarabine, denileukin diftitox, dexamethasone, DT PACE, docetaxel, dolastatin 10, Doxorubicin (Adriamycin®, Adriblastine), doxorubicin hydrochloride, enzastaurin, epoetin alfa, etoposide, Everolimus (RAD001), fenretinide, filgrastim, melphalan, mesna, Flavopiridol, Fludarabine (Fludara), Geldanamycin (17-AAG), ifosfamide, irinotecan hydrochloride, ixabepilone, Lenalidomide (Revlimid®, CC-5013), lymphokine-activated killer cells, melphalan, methotrexate, mitoxantrone hydrochloride, motexafin gadolinium, mycophenolate mofetil, nelarabine, oblimersen (Genasense) Obatoclax (GX15-070), oblimersen, octreotide acetate, omega-3 fatty acids, oxaliplatin, paclitaxel, PD0332991, PEGylated liposomal doxorubicin hydrochloride, pegfilgrastim, Pentstatin (Nipent), perifosine, Prednisolone, Prednisone, R-roscovitine (Selicilib, CYC202), recombinant interferon alfa, recombinant interleukin-12, recombinant interleukin-11, recombinant flt3 ligand, recombinant human thrombopoietin, rituximab, sargramostim, sildenafil citrate, simvastatin, sirolimus, Styryl sulphones, tacrolimus, tanespimycin, Temsirolimus (CCl-779), Thalidomide, therapeutic allogeneic lymphocytes, thiotepa, tipifarnib, Velcade® (bortezomib or PS-341), Vincristine (Oncovin), vincristine sulfate, vinorelbine ditartrate, Vorinostat (SAHA), vorinostat, and FR (fludarabine, rituximab), CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone), CVP (cyclophosphamide, vincristine and prednisone), FCM (fludarabine, cyclophosphamide, mitoxantrone), FCR (fludarabine, cyclophosphamide, rituximab), hyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, cytarabine), ICE (iphosphamide, carboplatin and etoposide), MCP (mitoxantrone, chlorambucil, and prednisolone), R-CHOP (rituximab plus CHOP), R-CVP (rituximab plus CVP), R-FCM (rituximab plus FCM), R-ICE (rituximab-ICE), and R-MCP (R-MCP).

The therapeutic treatments can be supplemented or combined with any of the abovementioned therapies with stem cell transplantation or treatment. One example of modified approach is radioimmunotherapy, wherein a monoclonal antibody is combined with a radioisotope particle, such as indium In 111, yttrium Y 90, iodine I-131. Examples of combination therapies include, but are not limited to, Iodine-131 tositumomab (Bexxar®), Yttrium-90 ibritumomab tiuxetan (Zevalin®), Bexxar® with CHOP.

Other therapeutic procedures include peripheral blood stem cell transplantation, autologous hematopoietic stem cell transplantation, autologous bone marrow transplantation, antibody therapy, biological therapy, enzyme inhibitor therapy, total body irradiation, infusion of stem cells, bone marrow ablation with stem cell support, in vitro-treated peripheral blood stem cell transplantation, umbilical cord blood transplantation, immunoenzyme technique, pharmacological study, low-LET cobalt-60 gamma ray therapy, bleomycin, conventional surgery, radiation therapy, and nonmyeloablative allogeneic hematopoietic stem cell transplantation.

In some embodiments, the methods include administering a compound of the formula described herein or a pharmaceutically acceptable salt, isomer, prodrug, or solvate thereof, in a therapeutically effective amount to a human in need thereof. The method can be employed to treat a patient who has or is believed to have a disease or condition whose symptoms or pathology is mediated by expression or activity of PI3Kβ and/or PI3Kδ. The patient may be a mammal or a human. In certain embodiment, the patient may be a human.

“Treatment” or “treating” is an approach for obtaining beneficial or desired results including clinical results. Beneficial or desired clinical results may include one or more of the following: a) inhibiting the disease or condition (e.g., decreasing one or more symptoms resulting from the disease or condition, and/or diminishing the extent of the disease or condition); b) slowing or arresting the development of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition, and/or preventing or delaying the spread (e.g., metastasis) of the disease or condition); and/or c) relieving the disease, that is, causing the regression of clinical symptoms (e.g., ameliorating the disease state, providing partial or total remission of the disease or condition, enhancing the effect of another medication, delaying the progression of the disease, increasing the quality of life, and/or prolonging survival.

“Prevention” or “preventing” mean any treatment of a disease or condition that causes the clinical symptoms of the disease or condition not to develop. Compounds may, in some embodiments, be administered to a subject (including a human) who is at risk or has a family history of the disease or condition.

“Subject” or “patient” refer to an animal, such as a mammal (including a human), that has been or will be the object of treatment, observation or experiment. The methods described herein may be useful in human therapy and/or veterinary applications. In some embodiments, the subject is a mammal. In one embodiment, the subject is a human. “Human in need thereof” refers to a human who may have or is suspect to have diseases, or disorders, or conditions that would benefit from certain treatment; for example, being treated with the PI3K inhibitor of the compounds according to the present application. In certain embodiments, the subject may be a human who (i) has not received any treatment including chemotherapy treatment, (ii) is substantially refractory to at least one chemotherapy treatment, (iii) is in relapse after treatment with chemotherapy, or both (i) and (ii). In some of embodiments, the subject is refractory to at least one, at least two, at least three, or at least four chemotherapy treatments (including standard or experimental chemotherapies).

The terms “therapeutically effective amount” or “effective amount” of a compound of the present application or a pharmaceutically acceptable salt, isomers, prodrug, or solvate thereof, mean an amount sufficient to effect treatment when administered to a subject, to provide a therapeutic benefit such as amelioration of symptoms or slowing of disease progression. For example, a therapeutically effective amount may be an amount sufficient to decrease a symptom of a disease or condition responsive to inhibition of PI3Kδ and PI3Kβ activity. The therapeutically effective amount may vary depending on the subject, and disease or condition being treated, the weight and age of the subject, the severity of the disease or condition, and the manner of administering, which can readily be determined by one or ordinary skill in the art.

In addition to the therapeutic uses, the compounds described herein have the selectivity or selective inhibition to certain PI3K isoforms. In one embodiment, the compounds have selectivity to PI3Kβ. In some embodiments, the compounds have selectivity to PI3Kδ. In yet other embodiments, the compounds have selectivity to PI3Kβ and PI3Kδ. The selectivity to PI3K isoforms may be determined by measuring the compound's activity in inhibiting certain PI3K isoforms using the assay described in the example below or the methods commonly used. It is understood that the conditions (e.g. the reagent concentration or the incubation temperature) may be varied and the results of the assay may vary. In some instances, the value may vary within a range of one to three-fold.

The term “inhibition” indicates a decrease in the baseline activity of a biological activity or process. The term “inhibition of activity of PI3K isoforms” or variants thereof refer to a decrease in activity in any PI3K isoform (e.g., alpha, beta, gamma, or delta) as a direct or indirect response to the presence of a compound of any of the formula described herein relative to the activity of PI3K isoform in the absence of such compound. “Inhibition of PI3Kδ and/or PI3Kβ activities” or variants thereof refer to a decrease in PI3Kδ and/or PI3Kβ activities as a direct or indirect response to the presence of the compounds described herein, relative to the activities of PI3Kδ and/or PI3Kβ in the absence of such compound. In some embodiments, the inhibition of PI3K isoform activities may be compared in the same subject prior to treatment, or other subjects not receiving the treatment.

Without being bound to any theory, the decrease in the activity of PI3K may be due to the direct interaction of the compound with PI3K, or due to the interaction of the compounds described herein with one or more other factors that affect PI3K activity. For example, the presence of the compounds may decrease the activities of PI3Kδ and/or PI3Kβ by directly binding to PI3Kδ and/or PI3Kβ, by causing (directly or indirectly) another factor to decrease PI3Kδ and/or PI3Kβ activities, or by (directly or indirectly) decreasing the amount of PI3Kδ and/or PI3Kβ present in the cell or organism.

The term “PI3K inhibitor” or variant thereof refers to a compound that inhibits the activity of PI3K. The term “PI3K isoform selective inhibitor” or variant thereof refers to a compound that inhibits the activity of one or more PI3K isoforms more effectively than the other remaining PI3K isoforms. By way of example, the term “PI3Kβ selective inhibitor” generally refers to a compound that inhibits the activity of the PI3Kβ isoform more effectively than other isoforms of the PI3K family, and the term “PI3Kδ selective inhibitor” generally refers to a compound that inhibits the activity of the PI3Kδ isoform more effectively than other isoforms of the PI3K family. The term “dual PI3Kδ/β selective inhibitor” generally refers to a compound that inhibits the activity of both PI3Kδ and PI3Kβ isoforms more effectively than other isoforms of the PI3K family (e.g., PI3Kα or γ).

The relative efficacies of compounds as inhibitors of an enzyme activity (or other biological activity) can be established by determining the concentrations at which each compound inhibits the activity to a predefined extent and then comparing the results. In one embodiment, the efficacy of a compound as an inhibitor of one or more PI3K isoforms can be measured by the compound concentration that inhibits 50% of the activity in a biochemical assay, i.e., the 50% inhibitory concentration or “IC₅₀”. The determination of IC₅₀ values can be accomplished using conventional techniques known in the art, including the techniques described in the Examples below. In general, an IC₅₀ can be determined by measuring the activity of a given enzyme in the presence of a range of concentrations of the compound under the study. The experimentally obtained values of enzyme activity may then be plotted against the compound concentrations used. The concentration of the inhibitor that shows 50% enzyme activity (as compared to the activity in the absence of any inhibitor) is taken as the IC₅₀ value. Analogously, other inhibitory concentrations can be defined through appropriate determinations of activity. For example, in some settings it may be desirable to establish a 90% inhibitory concentration, i.e., IC₉₀.

According to the present application, a PI3Kβ selective inhibitor is a compound that exhibits a 50% inhibitory concentration (IC₅₀) with respect to PI3Kβ that is at least 10-fold, at least 20-fold, at least 30-fold, at least 50-fold, at least 100-fold, at least 200-fold, or at least 500-fold lower than the IC₅₀ with respect to either PI3Kα or PI3Kγ or both PI3Kα and PI3Kγ. In addition, a PI3Kδ/β selective inhibitor is a compound that exhibits a 50% inhibitory concentration (IC₅₀) with respect to PI3Kβ and PI3Kδ that is at least 10-fold, at least 20-fold, at least 30-fold, at least 50-fold, at least 75-fold, at least 100-fold, at least 200-fold, and at least 500-fold lower than the IC₅₀ with respect to either PI3Kα or PI3Kγ. The dual PI3Kδ/β selective inhibitor may have the same or similar IC₅₀ to both PI3Kδ and PI3Kγ or may have different IC₅₀ to either PI3Kδ or PI3Kβ. As used herein, the term “potency,” “potent,” or variants thereof refer to the compound exhibiting an IC₅₀ value that is less than 100 nM. When comparing two compounds, the compound that exhibits a lower IC₅₀ value is referred to as a more potent inhibitor.

The compounds of the present application exhibit unexpected selectivity to PI3Kβ. As shown in the example, certain compounds in Table 1 exhibit low IC₅₀ values (e.g. 1 to 100 nM) to both PI3Kβ and PI3Kδ. Certain compounds in Table 1a also exhibited such selectivity to PI3K isoforms. Also, certain compounds of formula (I) exhibited at least between 10-fold to 400-fold lower IC₅₀ values for PI3Kβ than PI3Kγ, suggesting the compounds exhibit more selectivity to PI3Kβ compared to PI3Kγ (i.e., inhibits the activity of the PI3Kβ isoform more effectively than the PI3Kγ isoform as shown by the PI3Kβ/PI3Kβ ratio). Moreover, the compounds described herein exhibit selectivity to both PI3Kβ and PI3Kδ. The compound of (S)-2,4-diamino-6-((1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile, described in U.S. Provisional Application No. 61/745,437, exhibited less selectivity to PI3Kγ (e.g. the PI3Kγ/PI3Kβ ratio is less than 1-fold). The results of the present application suggest that certain compounds described herein are dual selective inhibitors of PI3Kδ and PI3Kβ and exhibit more selectivity to PI3Kβ compared to PI3Kγ. Each of the patents and the patent applications provided in the present application is hereby incorporated by reference in the entirety.

The methods described herein may be applied to cell populations in vivo or ex vivo. “In vivo” means within a living individual, as within an animal or human. In this context, the methods described herein may be used therapeutically in an individual. “Ex vivo” means outside of a living individual. Examples of ex vivo cell populations include in vitro cell cultures and biological samples including fluid or tissue samples obtained from individuals. Such samples may be obtained by methods well known in the art. Exemplary biological fluid samples include blood, cerebrospinal fluid, urine, and saliva. Exemplary tissue samples include tumors and biopsies thereof. In this context, the compounds may be used for a variety of purposes, including therapeutic and experimental purposes. For example, it may be used ex vivo to determine the optimal schedule and/or dosing of administration of a PI3K selective inhibitor for a given indication, cell type, individual, and other parameters. Information gleaned from such use may be used for experimental purposes or in the clinic to set protocols for in vivo treatment. Other ex vivo uses for which the invention may be suited are described below or will become apparent to those skilled in the art. The compounds of the formula described herein or a pharmaceutically acceptable salt, prodrug, or solvate thereof, may be further characterized to examine the safety or tolerance dosage in human or non-human subjects. Such properties may be examined using commonly known methods to those skilled in the art.

Compared to other PI3K isoforms, PI3Kδ is generally expressed in hematopoietic cells. Also, PI3Kβ is generally mis-regulated in certain cancer cells. Aberrant proliferation of cells often interferes with normal tissue function, which may result in abnormal cellular response such as immunity, inflammation, and/or apoptosis. The selective inhibitors to PI3Kδ and/or PI3Kβ are useful in treating, inhibiting, or preventing aberrant proliferation of cancerous and/or hematopoietic cells and ameliorating the symptoms and secondary conditions.

The compounds described herein may be used to treat subjects having various disease states, disorders, and conditions (also collectively referred to as “indications”) associated with PI3K isoforms or their activities. As used herein, the terms “diseases,” “disorders,” “conditions” are used interchangeably. Such indications may include, for example, cancer, including hematologic malignancies (e.g. leukemias and lymphomas, myeloproliferative disorders, myelodysplastic syndromes, plasma cell neoplasms) and solid tumors, inflammation, fibrosis, allergic conditions (including hypersensitivity), cardiovascular diseases, neurodegenerative diseases, renal disorders, viral infections, obesity, and autoimmune diseases.

In other embodiments, the compounds described herein may be used to treat cancers that are mediated by, dependent on, or associated with PI3K activity. In certain embodiments, the disease or condition is an autoimmune disease, an inflammatory disease, or a cancer. In some embodiments, the disease or condition is chosen from rheumatoid arthritis, osteoarthritis, atherosclerosis, psoriasis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, asthma, chronic obstructive airways disease, pneumonitis, dermatitis, alopecia, nephritis, vasculitis, atherosclerosis, Alzheimer's disease, hepatitis, primary biliary cirrhosis, sclerosing cholangitis, diabetes (including type I diabetes), acute rejection of transplanted organs, lymphomas, multiple myelomas, leukemias, neoplasms and solid tumors.

In other embodiments, the disease is a solid tumor. By way of examples, the solid tumor includes but is not limited to pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, prostate cancer, renal cancer, hepatocellular cancer, lung cancer, ovarian cancer, cervical cancer, rectum cancer, liver cancer, kidney cancer, stomach cancer, skin cancer, gastric cancer, esophageal cancer, head and neck cancer, melanoma, neuroendocrine cancers, CNS cancers (e.g., neuroblastoma), brain tumors (e.g., glioma, anaplastic oligodendroglioma, adult glioblastoma multiforme, and adult anaplastic astrocytoma), bone cancer, or soft tissue sarcoma. In some embodiments, the solid tumor is non-small cell lung cancer, small-cell lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, pancreatic cancer, prostate cancer, or breast cancer.

The present application also provides a method for treating a human in need thereof, who has or is suspected of having a disease or condition responsive or believed to be responsive to the inhibition of PI3Kδ and/or PI3Kβ activity by administering to the subject a compound of the formulae described herein or a pharmaceutically acceptable salt, enantiomer, atropisomer, tautomer, prodrug, or solvate thereof.

Additionally, the application provides a method of inhibiting kinase activity of a PI3Kδ and/or PI3Kβ polypeptides by contacting the polypeptides with a compound of the formulae described herein or a pharmaceutically acceptable salt, isomer, prodrug, solvate, or a mixture thereof.

Moreover, the application provides a method of decreasing cell viability, increasing cell death or apoptosis, increasing interference with PI3K signaling pathways (including AKT, S6RP, ERK phosphorylation), and/or reduction in chemokine production with an effective amount of a compound of any of the formulae described herein or a pharmaceutically acceptable salt, isomer, prodrug, solvate, or a mixture thereof.

The application further provides a method of disrupting leukocyte function comprising contacting the leukocytes with an effective amount of a compound of any of the formulae described herein or a pharmaceutically acceptable salt, isomer, prodrug, solvate, or a mixture thereof, in a human in need thereof.

Provided is also a method of inhibiting growth or proliferation of cancer cells comprising contacting the cancer cells with an effective amount of a compound of the formulae described herein or a pharmaceutically acceptable salt, isomer, prodrug, solvate, or a mixture thereof.

Kits

Provided herein are also kits that include a compound of the formulae of the present application or a pharmaceutically acceptable salt, isomer, prodrug, or solvate thereof, and suitable packaging. In one embodiment, a kit further includes instructions for use. In one aspect, a kit includes a compound of the formulae described herein or a pharmaceutically acceptable salt, isomer, prodrug, or solvate thereof, and a label and/or instructions for use of the compounds in the treatment of the indications, including the diseases or conditions, described herein.

Provided herein are also articles of manufacture that include a compound of any of the formulae described herein or a pharmaceutically acceptable salt, isomer, prodrug, or solvate thereof, in a suitable container. The container may be a vial, jar, ampoule, preloaded syringe, and intravenous bag.

Pharmaceutical Compositions and Modes of Administration

Compounds provided herein are usually administered in the form of pharmaceutical compositions. Thus, provides herein are also pharmaceutical compositions that contain one or more of the compounds of any of the formulae disclosed herein or a pharmaceutically acceptable salt, isomers, prodrug, or solvate thereof, and one or more pharmaceutically acceptable vehicles selected from carriers, adjuvants and excipients. Suitable pharmaceutically acceptable vehicles may include, for example, inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants. Such compositions are prepared in a manner well known in the pharmaceutical art. See, e.g., Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (G. S. Banker & C. T. Rhodes, Eds.).

The pharmaceutical compositions may be administered in either single or multiple doses. The pharmaceutical composition may be administered by various methods including, for example, rectal, buccal, intranasal and transdermal routes. In certain embodiments, the pharmaceutical composition may be administered by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant. In some embodiments, the pharmaceutical composition is administered orally.

One mode for administration is parenteral, for example, by injection. The forms in which the pharmaceutical compositions described herein may be incorporated for administration by injection include, for example, aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles.

Oral administration may be another route for administration of the compounds described herein. Administration may be via, for example, capsule or enteric coated tablets. In making the pharmaceutical compositions that include at least one compound of any of the formulae described herein or a pharmaceutically acceptable salt, prodrug, or solvate thereof, the active ingredient is usually diluted by an excipient and/or enclosed within such a carrier that can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be in the form of a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders. In certain embodiments, the pharmaceutical composition is in the form of tablets.

Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose. The formulations can additionally include lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl and propylhydroxy-benzoates; sweetening agents; and flavoring agents.

The compositions that include at least one compound of any of the formulae described herein or a pharmaceutically acceptable salt, isomer, prodrug, or solvate thereof, can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the subject by employing procedures known in the art. Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolutional systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are given in U.S. Pat. Nos. 3,845,770; 4,326,525; 4,902,514; and 5,616,345. Another formulation for use in the methods of the present invention employs transdermal delivery devices (“patches”). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds described herein in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Pat. Nos. 5,023,252, 4,992,445 and 5,001,139. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.

For preparing solid compositions such as tablets, the principal active ingredient may be mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of any of the above formulae or a pharmaceutically acceptable salt, prodrug, or solvate thereof. When referring to these preformulation compositions as homogeneous, the active ingredient may be dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.

The tablets or pills of the compounds described herein may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action, or to protect from the acid conditions of the stomach. For example, the tablet or pill can include an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.

Compositions for inhalation or insufflation may include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. In other embodiments, compositions in pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a facemask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner.

Dosing

The specific dose level of a compound of the formulae described herein for any particular subject will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease in the subject undergoing therapy. For example, a dosage may be expressed as a number of milligrams of a compound of the formula per kilogram of the subject's body weight (mg/kg). Dosages of between about 0.01 and 200 mg/kg may be appropriate. In some embodiments, about 0.01 and 150 mg/kg may be appropriate. In other embodiments a dosage of between 0.05 and 100 mg/kg may be appropriate. Normalizing according to the subject's body weight is particularly useful when adjusting dosages between subjects of widely disparate size, such as occurs when using the drug in both children and adult humans or when converting an effective dosage in a non-human subject such as dog to a dosage suitable for a human subject.

The daily dosage may also be described as a total amount of a compound of the formulae administered per dose or per day. Daily dosage of a compound may be between about 1 mg and 2,000 mg, between about 1,000 to 2,000 mg/day, between about 1 to 1,000 mg/day, between about 1 to 500 mg/day, between about 100 to 150 mg/day, between about 1 to 100 mg/day, between about between about 1 to 50 mg/day, between about 50 to 100 mg/day, between about 100 to 125 mg/day, between about 100 to 150 mg/day, between about 100 to 175 mg/day, between about 100 to 200 mg/day, between about 100 to 225 mg/day, between about 100 to 250 mg/day, between about 100 to 350 mg/day, between about 100 to 400 mg/day, between about 100 to 450 mg/day, or between about 100 to 500 mg/day.

When administered orally, the total daily dosage for a human subject may be between 1 mg and 1,000 mg/day, between about 1 to 100 mg/day, between about 1 to 50 mg/day, between about 50 to 100 mg/day, between 100 to 200 mg/day, between about 200 to 300 mg/day, between about 300 to 400 mg/day, between about 400 to 500 mg/day, between about 100 to 150 mg/day, between about 150 to 200 mg/day, between about 200 to 250 mg/day, between about 75 to 150 mg/day, or between about 150 to 300 mg/day.

The compounds of the present application or the compositions thereof may be administered once, twice, three, or four times daily, using any suitable mode described above. Also, administration or treatment with the compounds according to any of the formulae described herein may be continued for a number of days; for example, commonly treatment would continue for at least 7 days, 14 days, or 28 days, for one cycle of treatment. In some treatment, the compound or the composition thereof is administered continuously, i.e. every day. Treatment cycles are well known in cancer chemotherapy, and are frequently alternated with resting periods of about 1 to 28 days, commonly about 7 days or about 14 days, between cycles. The treatment cycles, in other embodiments, may also be continuous.

In a particular embodiment, the method comprises administering to the subject an initial daily dose of about 1 to 500 mg of a compound of the above formula and increasing the dose by increments until clinical efficacy is achieved. Increments of about 1, 5, 10, 25, 50, 75, or 100 mg can be used to increase the dose. The dosage can be increased daily, every other day, twice per week, or once per week.

Synthesis of the Compounds

The compounds of the present application may be prepared using the methods disclosed herein and routine modifications thereof, which will be apparent given the disclosure herein and methods well known in the art. Conventional and well-known synthetic methods may be used in addition to the teachings herein. The synthesis of typical compounds described herein may be accomplished as described in the following examples. If available, reagents may be purchased commercially, e.g., from Sigma Aldrich or other chemical suppliers. In general, compounds described herein are typically stable and isolatable at room temperature and pressure.

General Synthesis

Typical embodiments of compounds described herein may be synthesized using the general reaction schemes described below. It will be apparent given the description herein that the general schemes may be altered by substitution of the starting materials with other materials having similar structures to result in products that are correspondingly different. Descriptions of syntheses follow to provide numerous examples of how the starting materials may vary to provide corresponding products. Given a desired product for which the substituent groups are defined, the necessary starting materials generally may be determined by inspection. Starting materials are typically obtained from commercial sources or synthesized using published methods. For synthesizing compounds which are embodiments described in the present disclosure, inspection of the structure of the compound to be synthesized will provide the identity of each substituent group. The identity of the final product will generally render apparent the identity of the necessary starting materials by a simple process of inspection, given the examples herein.

Synthetic Reaction Parameters

The terms “solvent”, “inert organic solvent”, or “inert solvent” refer to a solvent inert under the conditions of the reaction being described in conjunction therewith (including, for example, benzene, toluene, acetonitrile, tetrahydrofuran (“THF”), dimethylformamide (“DMF”), chloroform, methylene chloride (or dichloromethane), diethyl ether, methanol, and the like). Unless specified to the contrary, the solvents used in the reactions of the present invention are inert organic solvents, and the reactions are carried out under an inert gas, preferably nitrogen.

The compounds of formula (J) may be prepared using the method shown in Reaction Scheme I. Also, the compounds of formula (I) may be prepared using the method shown below.

Step 1—Preparation of a Compound of Formula (1)

The compound of formula (1) can be made by treating 5-substituted-2,4,6-trihalopyrimidine (A) with ammonium hydroxide in a suitable solvent such as dioxane, where G is halo (e.g. iodo, bromo, chloro or fluoro). The reaction is carried out between 30° C. and 80° C. for between 2 and 8 hours or until the reaction is complete. Upon completion, water is added to the cooled solution, and the precipitate is collected by filtration. The nitrile may be converted to the carboxamide using commonly known methods.

Step 2—Preparation of a Compound of Formula (2)

The compound of formula (2) can be made by combining compounds (B), (C) and (D) in the presence of a dehydrating agent. Compounds (B), (C) and (D) may be obtained commercially or made by the methods known in the art. X, Y, Z, n, m′, R¹, R², R³, and R⁵ are defined as above. Compound (B) is mixed with Compound (D) in the presence of a coupling agent such as diphenyl phosphite in a solvent such as pyridine. After stirring at a temperature between ambient (i.e. room temperature) and 100° C. for between 1 and 5 hours, compound (C) is added. After further stirring at a temperature between ambient and 100° C. for between 5 and 24 hours, the reaction mixture is cooled to room temperature. To extract the compound of formula (2), an organic solvent such as ethyl acetate (EtOAc) may be added, followed by washing with mild base, water, and brine. The organic phase may be concentrated to obtain the compound of formula (2). The compound of formula (2) may be purified by any suitable method known in the art, such as chromatography on silica gel. Alternatively, the compound of formula (2) is purified directly without an aqueous work-up. Alternatively, the compound of formula (2) may be used in the next step without purification. Alkylsulfonyl and cyano compounds may be prepared using commonly known methods by displacing a halogen from the corresponding halogen containing compounds. In some cases, compounds (C) may be protected with groups such as triphenylmethyl, Boc, or trimethylsilyloxymethyl and removed in a subsequent step by commonly known methods.

Step 3—Preparation of a Compound of Formula (3)

The compound of formula (3) can be made by removing the protecting group(s) from the compound of formula (2). The compound of formula (2) is dissolved in a suitable solvent and treated (i.e. mixed) with a suitable acid. Suitable solvents may include, for example, dichloromethane, dioxane, or other suitable solvents. Suitable acids may include, for example, trifluoroacetic acid or hydrochloric acid. The reaction may be carried out at temperatures between −78° C. to ambient temperature. On reaction completion, solvent is removed to obtain the compound of formula (3).

Step 4—Preparation of a Compound of Formula (1)

The compound of formula (I-1) may generally be prepared by coupling compound of formula (3) and compound of formula (1) in the presence of a suitable base in a suitable solvent. Also, the compound of formula (J), wherein A is a single bond, may generally be prepared by coupling compound of formula (3) and compound of formula (1) in the presence of a suitable base in a suitable solvent. A suitable base may be by example, diisopropylethylamine. A suitable solvent may by example be isopropanol (IPA), DMSO, DMF, ethylene glycol, or ethanol. The reaction is typically performed at a temperature between 50° C. to 150° C. for about 30 minutes to 24 hours. Alternatively, the reaction may be conducted by microwave at a temperature between 100° C. to 150° C. for about 30 minutes to 24 hours. Alternatively, the reaction may be carried out in a sealed tube at a temperature between 50° C. to 150° C. The compound of formula (I-2) may generally be prepared by coupling a compound of formula (3) with a suitable acid in the presence of a coupling agent, such as HATU, DCC, or carbonyl diimidazole in the presence of a base such as triethylamine or diisopropylethylamine in a suitable solvent such as dichloromethane or THF. In addition, the compound of formula (I-2), wherein A is C(O), may generally be prepared by coupling a compound of formula (3) with a suitable acid in the presence of a coupling agent, such as HATU, DCC, or carbonyl diimidazole in the presence of a base such as triethylamine or diisopropylethylamine in a suitable solvent such as dichloromethane or THF. The resulting compound may be isolated by methods known in the art; for example, by removal of solvent under reduced pressure or aqueous work-up. The product may be purified using any suitable methods known in the art; for example, chromatography of the residue on a silica column, chromatography on an HPLC, or crystallization.

After synthesis, the compounds may be isolated in the form of a free base or a salt (which includes and is not limited to a hydrochloric acid salt form or a trifluoroacetic acid salt form) and characterized by NMR. Thus, the resulting compounds and their NMR characterizations may be either the free base or salt. The ratio of parent and corresponding salt is not determined.

Example 1 Preparation of a Compound of Formula (1)

A. Preparation of a compound of formula (1) where R^(4′) is CN and G is Cl (2,4-diamino-6-chloropyrimidine-5-carbonitrile)

Ammonium hydroxide (20 mL) was added to a solution of 2,4,6-trichloropyrimidine-5-carbonitrile (5.0 g, 24 mmol) in dioxane (20 mL) at room temperature. The solution was warmed to 50° C. and stirred for 3 hours. The reaction mixture was cooled to 10° C. and water (50 mL) added. The resulting solid was filtered, washed with water, and dried under high vacuum to afford 2,4-diamino-6-chloropyrimidine-5-carbonitrile. ¹³H NMR (100 MHz, DMSO) 164.8, 162.6, 161.9, 115.8, 77.6. ES/MS m/z=169.9 (M+H⁺).

B. Preparation of the below compound of formula (1), using the method described in Example 1A and Reaction Theme I

-   5-chloro-6-fluoropyrimidine-2,4-diamine

Example 2 Preparation of Compounds of Formula (2)

A. Preparation of a compound of formula (2) where n is 1, R¹ is chloro, Y is N, Z is CH, X is C and the attachment point with the quinazolinone, m′ is 0, R³ is CH₂CH₃, and R⁵ is hydrogen

Diphenyl phosphite (1.6 mL, 8.2 mmol) was added to a solution of 2-amino-6-chlorobenzoic acid (400 mg, 2.3 mmol) and (S)-2-(tert-butoxycarbonylamino)butanoic acid (616 mg, 3.0 mmol) in pyridine (2 mL). The reaction mixture was stirred at 40° C. for 2 hours and 3-aminopyrazole (232 mg, 2.8 mmol) was then added to the mixture. The reaction was stirred at 50° C. for 16 hours and cooled to room temperature. The mixture was diluted with EtOAc (50 mL), washed with saturated aqueous NaHCO₃ (1×50 mL), brine (50 mL), and dried over magnesium sulfate. The organic layer was filtered and concentrated in vacuo to afford material which was purified by column chromatography on SiO₂ eluting with EtOAc in hexanes (10-70%) to afford (S)-tert-butyl (1-(5-chloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)propyl)carbamate. ES/MS m/z=404.1 (M+H⁺).

B. Preparation of the below compounds of formula (2) using the method described in Example 2A and Reaction Theme I:

-   (S)-tert-butyl     (1-(5-chloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)carbamate; -   (S)-tert-butyl     (cyclopropyl(5-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)methyl)carbamate; -   (S)-tert-butyl     (cyclopropyl(5,8-difluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)methyl)carbamate; -   (S)-tert-butyl     (cyclopropyl(8-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)methyl)carbamate; -   (S)-tert-butyl     ((8-chloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)(cyclopropyl)methyl)carbamate; -   (S)-tert-butyl     ((5-chloro-3-(5-chloro-1H-pyrazol-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)(cyclopropyl)methyl)carbamate; -   (S)-tert-butyl     (1-(5-chloro-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazolin-2-yl)ethyl)carbamate; -   (S)-tert-butyl     ((5-chloro-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazolin-2-yl)(cyclopropyl)methyl)carbamate; -   (S)-tert-butyl     ((5-chloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)(cyclopropyl)methyl)carbamate; -   (S)-tert-butyl     (1-(5-chloro-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazolin-2-yl)propyl)carbamate; -   (S)-tert-butyl     (1-(5-chloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)propyl)carbamate; -   (S)-tert-butyl     2-(5-chloro-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazolin-2-yl)pyrrolidine-1-carboxylate; -   (S)-tert-butyl     2-(5-chloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)pyrrolidine-1-carboxylate; -   (S)-tert-butyl     ((8-chloro-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazolin-2-yl)(cyclopropyl)methyl)carbamate; -   (S)-tert-butyl     (cyclopropyl(5,8-dichloro-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazolin-2-yl)methyl)carbamate; -   (S)-tert-butyl     (cyclopropyl(5,8-dichloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)methyl)carbamate; -   (S)-tert-butyl     (1-(8-methyl-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazolin-2-yl)propyl)carbamate; -   (S)-tert-butyl     (1-(8-methyl-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)propyl)carbamate; -   (S)-tert-butyl     (1-(5-fluoro-8-methyl-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazolin-2-yl)propyl)carbamate; -   (S)-tert-butyl     (1-(5-fluoro-8-methyl-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)propyl)carbamate; -   (S)-tert-butyl     (1-(5,8-dichloro-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazolin-2-yl)propyl)carbamate; -   (S)-tert-butyl     (1-(5,8-dichloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)propyl)carbamate; -   (R)-tert-butyl     (2-(benzyloxy)-1-(5-chloro-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazolin-2-yl)ethyl)carbamate; -   (R)-tert-butyl     (2-(benzyloxy)-1-(5-chloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)carbamate; -   (S)-tert-butyl     (1-(5-chloro-3-(5-(3-methoxypropyl)-1H-pyrazol-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)propyl)carbamate; -   (R)-tert-butyl     (1-(5-chloro-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazolin-2-yl)-2-hydroxyethyl)carbamate; -   (R)-tert-butyl     (1-(5-chloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)-2-hydroxyethyl)carbamate; -   (S)-tert-butyl     (1-(5-chloro-8-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)carbamate; -   (S)-tert-butyl     (1-(5-chloro-8-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)propyl)carbamate; -   (S)-tert-butyl     (1-(5,8-dichloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)carbamate; -   (S)-tert-butyl     ((5-chloro-8-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)(cyclopropyl)methyl)carbamate; -   (S)-tert-butyl     (1-(5-bromo-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)propyl)carbamate; -   (S)-tert-butyl     (1-(8-iodo-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)propyl)carbamate; -   (S)-tert-butyl     (1-(3-(4-bromo-1H-pyrazol-3-yl)-5-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)propyl)carbamate; -   (S)-tert-butyl     (1-(5-bromo-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazolin-2-yl)propyl)carbamate; -   (S)-tert-butyl     (1-(3-(4-bromo-1H-pyrazol-3-yl)-5-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate; -   (S)-tert-butyl     (1-(3-(4-bromo-1H-pyrazol-3-yl)-5,8-dichloro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate; -   (S)-tert-butyl     (1-(3-(4-bromo-1H-pyrazol-3-yl)-5,8-dichloro-4-oxo-3,4-dihydroquinazolin-2-yl)propyl)carbamate; -   (S)-tert-butyl     (1-(8-iodo-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazolin-2-yl)propyl)carbamate; -   (S)-tert-butyl     ((5-chloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)(phenyl)methyl)carbamate; -   (S)-tert-butyl     ((5-chloro-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazolin-2-yl)(phenyl)methyl)carbamate; -   (S)-tert-butyl     (1-(6-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)carbamate; -   (S)-tert-butyl     (1-(6-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)propyl)carbamate; -   (S)-tert-butyl     (cyclopropyl(6-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)methyl)carbamate; -   (S)-tert-butyl     (1-(5-chloro-3-(4-methyl-1H-pyrazol-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate; -   (S)-tert-butyl     (1-(5-chloro-3-(5-isobutyl-1H-pyrazol-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate; -   (S)-tert-butyl     (1-(5-chloro-3-(5-cyclopropyl-1H-pyrazol-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate; -   (S)-tert-butyl     (1-(5-chloro-4-oxo-3-(5-(trifluoromethyl)-1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)carbamate; -   (S)-tert-butyl     (1-(5-chloro-3-(5-methyl-1H-pyrazol-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate; -   (S)-tert-butyl     (1-(8-chloro-6-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)carbamate; -   (S)-tert-butyl     (1-(5-chloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)butyl)carbamate; -   (S)-tert-butyl     (1-(5-(difluoromethyl)-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)carbamate; -   (S)-tert-butyl     ((5-chloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)(cyclobutyl)methyl)carbamate; -   (S)-tert-butyl     ((8-chloro-6-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)(cyclobutyl)methyl)carbamate; -   (S)-tert-butyl     (cyclobutyl(5-(difluoromethyl)-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)methyl)carbamate; -   (S)-tert-butyl     (1-(4-oxo-3-(1H-pyrazol-3-yl)-8-(trifluoromethyl)-3,4-dihydroquinazolin-2-yl)ethyl)carbamate; -   (S)-tert-butyl     (cyclopropyl(4-oxo-3-(1H-pyrazol-3-yl)-8-(trifluoromethyl)-3,4-dihydroquinazolin-2-yl)methyl)carbamate; -   (S)-tert-butyl     (1-(6-chloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)carbamate; -   (S)-tert-butyl     (1-(7-chloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)carbamate; -   (S)-tert-butyl     (1-(8-(difluoromethyl)-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)carbamate; -   (S)-tert-butyl     (1-(8-(difluoromethyl)-6-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)carbamate; -   (S)-tert-butyl     ((8-chloro-5-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)(cyclopropyl)methyl)carbamate; -   (S)-tert-butyl     (1-(5-chloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)-2-methylpropyl)carbamate; -   (S)-tert-butyl     (1-(8-chloro-5-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)carbamate; -   (S)-tert-butyl     (cyclopropyl(8-(difluoromethyl)-6-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)methyl)carbamate; -   (R)-tert-butyl     (2-(benzyloxy)-1-(8-chloro-6-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)carbamate; -   (S)-tert-butyl     (1-(5,8-difluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)carbamate; -   (S)-tert-butyl     (1-(5-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)carbamate; -   (S)-tert-butyl     (1-(8-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;     (S)-tert-butyl     (1-(5,8-dichloro-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazolin-2-yl)ethyl)carbamate; -   (S)-tert-butyl     (1-(5-chloro-3-(5-chloro-1H-pyrazol-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate; -   (S)-tert-butyl     (1-(5-chloro-3-(5-fluoro-1H-pyrazol-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate; -   (S)-tert-butyl     (1-(8-chloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)carbamate; -   (R)-tert-butyl     ((5-chloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)(cyclopropyl)methyl)carbamate; -   (S)-tert-butyl     (1-(5-chloro-8-fluoro-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazolin-2-yl)ethyl)carbamate; -   (S)-tert-butyl     (1-(6,8-difluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)carbamate; -   (S)-tert-butyl     (cyclopropyl(6,8-difluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)methyl)carbamate; -   (R)-tert-butyl     (1-(8-chloro-6-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)carbamate; -   (S)-tert-butyl     (1-(4-oxo-3-(1H-pyrazol-3-yl)-5-(trifluoromethyl)-3,4-dihydroquinazolin-2-yl)ethyl)carbamate; -   (S)-tert-butyl     (1-(5-(difluoromethyl)-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazolin-2-yl)ethyl)carbamate; -   (S)-tert-butyl     (cyclopropyl(5-(difluoromethyl)-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)methyl)carbamate; -   (R)-tert-butyl     (1-(5-(difluoromethyl)-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)carbamate; -   (S)-tert-butyl     ((8-chloro-6-fluoro-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazolin-2-yl)(cyclopropyl)methyl)carbamate; -   (S)-tert-butyl     (1-(8-chloro-6-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)propyl)carbamate; -   (S)-tert-butyl     (1-(8-chloro-6-fluoro-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazolin-2-yl)ethyl)carbamate; -   (S)-tert-butyl     (1-(3-(5-amino-1H-pyrazol-3-yl)-5-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate; -   (S)-tert-butyl     ((8-bromo-3-(4-methyl-1H-pyrazol-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)(cyclopropyl)methyl)carbamate; -   (S)-tert-butyl     (1-(4-oxo-3-(1H-pyrazol-4-yl)-5-(trifluoromethyl)-3,4-dihydroquinazolin-2-yl)ethyl)carbamate; -   (S)-tert-butyl     (1-(5-chloro-3-(3-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate; -   (S)-tert-butyl     (cyclopropyl(4-oxo-3-(1H-pyrazol-3-yl)-5-(trifluoromethyl)-3,4-dihydroquinazolin-2-yl)methyl)carbamate; -   (S)-tert-butyl     ((8-chloro-6-fluoro-3-(3-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)(cyclopropyl)methyl)carbamate; -   (S)-tert-butyl     (1-(5,8-dichloro-3-(3-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate; -   (S)-tert-butyl     (1-(8-chloro-5-(difluoromethyl)-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)carbamate; -   (S)-tert-butyl     (1-(8-chloro-5-methyl-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;     (S)-tert-butyl     (1-(5,7-difluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)carbamate; -   (S)-tert-butyl     (1-(5-chloro-7-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)carbamate; -   (S)-tert-butyl     (1-(6-chloro-5-(difluoromethyl)-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)carbamate; -   (S)-tert-butyl     (1-(7,8-difluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)carbamate; -   (S)-tert-butyl     ((5-chloro-3-(4-methyl-1H-pyrazol-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)(cyclopropyl)methyl)carbamate; -   (S)-tert-butyl     ((5-chloro-7-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)(cyclopropyl)methyl)carbamate; -   (S)-tert-butyl     (1-(5,8-dichloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)butyl)carbamate; -   (S)-tert-butyl     (1-(5,8-dichloro-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazolin-2-yl)butyl)carbamate; -   (S)-tert-butyl     (1-(5-chloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)butyl)carbamate; -   (S)-tert-butyl     (1-(5-chloro-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazolin-2-yl)butyl)carbamate; -   (S)-tert-butyl     ((5-chloro-6-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)(cyclopropyl)methyl)carbamate; -   (S)-tert-butyl     (1-(5-chloro-6-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)carbamate; -   (S)-tert-butyl     (1-(5-chloro-6-fluoro-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazolin-2-yl)ethyl)carbamate; -   (S)-tert-butyl     (1-(8-chloro-6-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)propyl)carbamate; -   (S)-tert-butyl     ((8-chloro-6-fluoro-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazolin-2-yl)(cyclopropyl)methyl)carbamate; -   (S)-tert-butyl     (1-(3-(4-bromo-1H-pyrazol-3-yl)-8-chloro-6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate; -   (S)-tert-butyl     (1-(5-chloro-6-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)butyl)carbamate; -   (S)-tert-butyl     (1-(8-chloro-6-fluoro-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazolin-2-yl)ethyl)carbamate; -   (S)-tert-butyl     (1-(8-bromo-6-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)carbamate; -   (S)-tert-butyl     ((8-bromo-6-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)(cyclopropyl)methyl)carbamate; -   (S)-tert-butyl     (1-(4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)carbamate; -   (S)-tert-butyl     ((8-chloro-6-fluoro-4-oxo-3-(1-trityl-1H-imidazol-4-yl)-3,4-dihydroquinazolin-2-yl)(cyclopropyl)methyl)carbamate; -   (S)-tert-butyl     (1-(5-chloro-4-oxo-3-(1-trityl-1H-imidazol-4-yl)-3,4-dihydroquinazolin-2-yl)butyl)carbamate; -   (S)-tert-butyl     (1-(8-chloro-6-fluoro-4-oxo-3-(1-trityl-1H-imidazol-4-yl)-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;     (S)-tert-butyl     (1-(5,8-dichloro-4-oxo-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)-3,4-dihydroquinazolin-2-yl)ethyl)carbamate.     ES/MS 554.2 (M+H⁺); -   (S)-tert-butyl     (1-(5-chloro-4-oxo-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)-3,4-dihydroquinazolin-2-yl)ethyl)carbamate.     ES/MS 520.2 (M+H⁺); -   (S)-tert-butyl     ((5-chloro-4-oxo-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)-3,4-dihydroquinazolin-2-yl)(cyclopropyl)methyl)carbamate.     ES/MS 546.2 (M+H⁺); and -   (S)-tert-butyl     (1-(5-chloro-4-oxo-3-(1H-pyrrol-2-yl)-3,4-dihydroquinazolin-2-yl)ethyl)carbamate.

C. Preparation of a compound of formula (2) where n is 1, R¹ is SO₂CH₃, Y is N, Z is CH, X is C and the attachment point with the quinazolinone, m′ is 0, R⁵ is hydrogen, and R′ is CH₂CH₃

In a solution of(S)-tert-butyl (1-(5-bromo-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)propyl)carbamate (300 mg, 0.67 mmol) in DMSO (3 mL), sodium methanesulfinate (266 mg, 2.6 mmol), cesium carbonate (125 mg, 0.39 mmol), copper iodide (57 mg, 0.30 mmol) and (S)-proline (62 mg, 0.54 mmol) were added. The resulting mixture was degassed under Argon, sealed, and heated to 80° C. After 18 hours, the reaction was cooled, poured into EtOAc, and washed with H₂O. The organic phase was purified by column chromatography on silica eluting with EtOAc in hexanes (0-100%) to afford (S)-tert-butyl (1-(5-(methylsulfonyl)-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)propyl)carbamate. ES/MS m/z=448.1 (M+H⁺).

D. Preparation of a compound of formula (2) in which n is 1, R¹ is CN, Y is N, X is CH, Z is C and the attachment point with the quinazolinone, m′ is 0, R⁵ is hydrogen, and R³ is CH₂CH₃

(S)-tert-butyl (1-(5-bromo-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)propyl)carbamate (400 mg, 0.89 mmol), zinc cyanide (126 mg, 1.07 mmol), and tetrakis(triphenylphosphine)palladium(0) (103 mg, 0.09 mmol) were combined in NMP and degassed under Argon. The resulting solution was heated to 120° C. with a microwave for 2 hours. Upon cooling, the reaction was poured into EtOAc and washed with satd. aq. NaHCO₃ (3×). The solvent was removed in vacuo from the organic phase and the residue was purified by column chromatography on silica eluting with EtOAc in hexanes (0-100%) to afford (S)-tert-butyl (1-(5-cyano-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)propyl)carbamate. ES/MS m/z=394.9 (M+H⁺).

E. Preparation of the below compound of formula (2) using the above methods:

(S)-tert-butyl (1-(5-cyano-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazolin-2-yl)propyl)carbamate. One method was described in Example 2D and Reaction Theme I.

F. Preparation of a compound of formula (2) where n is 1, R¹ is CN, Y is N, X is CH, Z is C and the attachment point with the quinazolinone, m′ is 0, R⁵ is hydrogen, and R³ is CH₂CH₃

(S)-tert-butyl (1-(8-iodo-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)propyl)carbamate (500 mg, 1.01 mmol), zinc cyanide (142 mg, 1.21 mmol), and tetrakis(triphenylphosphine)palladium(0) (117 mg, 0.10 mmol) were combined in NMP (4 mL) and degassed under Argon. The resulting solution was heated to 80° C. and stirred at that temperature for 18 hours. Upon cooling, the reaction was poured into EtOAc and washed with satd. aq. NaHCO₃ (2×). The organic phase was concentrated in vacuo and the residue purified by column chromatography on silica eluting with EtOAc in hexanes (0-100%) to afford (S)-tert-butyl (1-(8-cyano-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)propyl)carbamate. ES/MS m/z=394.9 (M+H⁺).

G. Preparation of the below compound of formula (2) using the methods described in Example 2F and Reaction Theme 1:

-   (S)-tert-butyl     (1-(8-cyano-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazolin-2-yl)propyl)carbamate; -   (S)-tert-butyl     ((8-cyano-3-(4-methyl-1H-pyrazol-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)(cyclopropyl)methyl)carbamate; -   (S)-tert-butyl     (1-(8-cyano-6-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;     and -   (S)-tert-butyl     ((8-cyano-6-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)(cyclopropyl)methyl)carbamate;

H. Preparation of a compound of formula (2) where n is 1, R¹ is cyclopropyl, Y is N, Z is CH, X is C and the attachment point with the quinazolinone, m′ is 0, R⁵ is hydrogen, and R³ is CH₂CH₃

(S)-tert-butyl (1-(5-bromo-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)propyl)carbamate (250 mg, 0.56 mmol), cyclopropylboronic acid (118 mg, 1.4 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (70 mg, 0.1 mmol), XPhos Pd G2 (50 mg, 0.03 mmol), and cesium carbonate (545 mg, 1.7 mmol) were combined in a 4:1 mixture of dioxane:water. The mixture was degassed under Argon and heated to 100° C. for 3 days. The crude reaction mixture was adsorbed to isolute and purified by silica gel chromatography (24 g column, 0-70% EtOAc/hexane) to give (S)-tert-butyl (1-(5-cyclopropyl-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)propyl)carbamate.

H. Preparation of a compound of formula (2) where n is 1, R¹ is Cl, Y is N, X is CH, Z is C and the attachment point with the quinazolinone, m′ is 0, R⁵ is hydrogen, and R³ is CH₂OH

Ten percent of Palladium on carbon (100 mg) was added to a solution of (R)-tert-butyl (2-(benzyloxy)-1-(5-chloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)carbamate (500 mg, 1.01 mmol) in 1:1 ethyl acetate/methanol (10 mL). The reaction mixture was stirred under a hydrogen atmosphere for 6 hours and filtered over Celite and concentrated to afford (R)-tert-butyl (1-(5-chloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)-2-hydroxyethyl)carbamate. ES/MS m/z=406.1 (M+H⁺).

I. Preparation of the below compound of Formula (2) using the methods described in Example 2H and Reaction Scheme 1:

-   (R)-tert-butyl     (1-(5-chloro-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazolin-2-yl)-2-hydroxyethyl)carbamate.     (R)-tert-butyl     (1-(8-chloro-6-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)-2-hydroxyethyl)carbamate.

Example 3 Preparation of Compounds of Formula (3)

A. Preparation of a compound of formula (3) where n is 1, R¹ is chloro, Y is N, X is CH, Z is C and the attachment point with the quinazolinone, m′ is 0, R⁵ is hydrogen, and R³ is CH₂CH₃

Trifluoroacetic acid (0.4 mL) was added to a suspension of(S)-tert-butyl (1-(5-chloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)propyl)carbamate (100 mg, 0.25 mmol) in dichloromethane (1.6 mL). The solution was stirred at room temperature for 3 hours and concentrated in vacuo to afford (S)-2-(1-aminopropyl)-5-chloro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one 2,2,2-trifluoroacetic acid salt. ES/MS m/z=304.1 (M+H⁺).

B. Preparation of the below compounds of formula (3) using the methods in Example 3A and Reaction Theme 1:

-   (S)-2-(1-aminoethyl)-5-chloro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; -   (S)-2-(amino(cyclopropyl)methyl)-5-fluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; -   (S)-2-(amino(cyclopropyl)methyl)-5,8-difluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; -   (S)-2-(amino(cyclopropyl)methyl)-8-fluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; -   (S)-2-(amino(cyclopropyl)methyl)-8-chloro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; -   (S)-2-(amino(cyclopropyl)methyl)-5-chloro-3-(5-chloro-1H-pyrazol-3-yl)quinazolin-4(3H)-one; -   (S)-2-(1-aminoethyl)-5-chloro-3-(1H-pyrazol-4-yl)quinazolin-4(3H)-one; -   (S)-2-(amino(cyclopropyl)methyl)-5-chloro-3-(1H-pyrazol-4-yl)quinazolin-4(3H)-one; -   (S)-2-(amino(cyclopropyl)methyl)-5-chloro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; -   (S)-2-(1-aminopropyl)-5-chloro-3-(1H-pyrazol-4-yl)quinazolin-4(3H)-one; -   (S)-2-(1-aminopropyl)-5-chloro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; -   (S)-5-chloro-3-(1H-pyrazol-4-yl)-2-(pyrrolidin-2-yl)quinazolin-4(3H)-one; -   (S)-5-chloro-3-(1H-pyrazol-3-yl)-2-(pyrrolidin-2-yl)quinazolin-4(3H)-one; -   (S)-2-(amino(cyclopropyl)methyl)-8-chloro-3-(1H-pyrazol-4-yl)quinazolin-4(3H)-one; -   (S)-2-(amino(cyclopropyl)methyl)-5,8-dichloro-3-(1H-pyrazol-4-yl)quinazolin-4(3H)-one; -   (S)-2-(amino(cyclopropyl)methyl)-5,8-dichloro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; -   (S)-2-(1-aminopropyl)-8-methyl-3-(1H-pyrazol-4-yl)quinazolin-4(3H)-one; -   (S)-2-(1-aminopropyl)-8-methyl-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; -   (S)-2-(1-aminopropyl)-5-fluoro-8-methyl-3-(1H-pyrazol-4-yl)quinazolin-4(3H)-one; -   (S)-2-(1-aminopropyl)-5-fluoro-8-methyl-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; -   (S)-2-(1-aminopropyl)-5,8-dichloro-3-(1H-pyrazol-4-yl)quinazolin-4(3H)-one; -   (S)-2-(1-aminopropyl)-5,8-dichloro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; -   (R)-2-(1-amino-2-(benzyloxy)ethyl)-5-chloro-3-(1H-pyrazol-4-yl)quinazolin-4(3H)-one; -   (R)-2-(1-amino-2-(benzyloxy)ethyl)-5-chloro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; -   (S)-2-(1-aminopropyl)-5-chloro-3-(5-(3-methoxypropyl)-1H-pyrazol-3-yl)quinazolin-4(3H)-one; -   (R)-2-(1-amino-2-hydroxyethyl)-5-chloro-3-(1H-pyrazol-4-yl)quinazolin-4(3H)-one; -   (R)-2-(1-amino-2-hydroxyethyl)-5-chloro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; -   (S)-2-(1-aminoethyl)-5-chloro-8-fluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; -   (S)-2-(1-aminopropyl)-5-chloro-8-fluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; -   (S)-2-(1-aminoethyl)-5,8-dichloro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; -   (S)-2-(amino(cyclopropyl)methyl)-5-chloro-8-fluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; -   (S)-2-(1-aminopropyl)-5-bromo-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; -   (S)-2-(1-aminopropyl)-3-(4-bromo-1H-pyrazol-3-yl)-5-chloroquinazolin-4(3H)-one; -   (S)-2-(1-aminopropyl)-5-bromo-3-(1H-pyrazol-4-yl)quinazolin-4(3H)-one; -   (S)-2-(1-aminoethyl)-3-(4-bromo-1H-pyrazol-3-yl)-5-chloroquinazolin-4(3H)-one; -   (S)-2-(1-aminoethyl)-3-(4-bromo-1H-pyrazol-3-yl)-5,8-dichloroquinazolin-4(3H)-one; -   (S)-2-(1-aminopropyl)-3-(4-bromo-1H-pyrazol-3-yl)-5,8-dichloroquinazolin-4(3H)-one; -   (S)-2-(amino(phenyl)methyl)-5-chloro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; -   (S)-2-(amino(phenyl)methyl)-5-chloro-3-(1H-pyrazol-4-yl)quinazolin-4(3H)-one; -   (S)-2-(1-aminoethyl)-6-fluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; -   (S)-2-(1-aminopropyl)-6-fluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; -   (S)-2-(amino(cyclopropyl)methyl)-6-fluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; -   (S)-2-(1-aminoethyl)-5-chloro-3-(4-methyl-1H-pyrazol-3-yl)quinazolin-4(3H)-one; -   (S)-2-(1-aminoethyl)-5-chloro-3-(5-isobutyl-1H-pyrazol-3-yl)quinazolin-4(3H)-one; -   (S)-2-(1-aminoethyl)-5-chloro-3-(5-cyclopropyl-1H-pyrazol-3-yl)quinazolin-4(3H)-one; -   (S)-2-(1-aminoethyl)-5-chloro-3-(5-(trifluoromethyl)-1H-pyrazol-3-yl)quinazolin-4(3H)-one; -   (S)-2-(1-aminoethyl)-5-chloro-3-(5-methyl-1H-pyrazol-3-yl)quinazolin-4(3H)-one; -   (S)-2-(1-aminopropyl)-5-(methylsulfonyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; -   (S)-2-(1-aminopropyl)-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazoline-5-carbonitrile; -   (S)-2-(1-aminopropyl)-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazoline-5-carbonitrile; -   (S)-2-(1-aminopropyl)-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazoline-8-carbonitrile; -   ((S)-2-(1-aminopropyl)-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazoline-8-carbonitrile; -   (S)-2-(1-aminoethyl)-8-chloro-6-fluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; -   (S)-2-(1-aminobutyl)-5-chloro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; -   (S)-2-(1-aminoethyl)-5-(difluoromethyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; -   (S)-2-(amino(cyclobutyl)methyl)-5-(difluoromethyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; -   (S)-2-(amino(cyclobutyl)methyl)-5-chloro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; -   (S)-2-(amino(cyclobutyl)methyl)-8-chloro-6-fluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; -   (S)-2-(1-aminoethyl)-3-(1H-pyrazol-3-yl)-8-(trifluoromethyl)quinazolin-4(3H)-one; -   (S)-2-(amino(cyclopropyl)methyl)-3-(1H-pyrazol-3-yl)-8-(trifluoromethyl)quinazolin-4(3H)-one; -   (S)-2-(1-aminoethyl)-6-chloro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; -   (S)-2-(1-aminoethyl)-7-chloro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; -   (S)-2-(1-aminoethyl)-8-(difluoromethyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; -   (S)-2-(1-aminoethyl)-8-(difluoromethyl)-6-fluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; -   (S)-2-(1-amino-2-methylpropyl)-5-chloro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; -   (S)-2-(1-aminoethyl)-8-chloro-5-fluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; -   (S)-2-(amino(cyclopropyl)methyl)-8-(difluoromethyl)-6-fluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; -   (S)-2-(amino(cyclopropyl)methyl)-8-chloro-5-fluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; -   (R)-2-(1-amino-2-hydroxyethyl)-8-chloro-6-fluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; -   (S)-2-(1-aminoethyl)-5,8-difluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; -   (S)-2-(1-aminoethyl)-5-fluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; -   (S)-2-(1-aminoethyl)-8-fluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one;     (S)-2-(1-aminoethyl)-5,8-dichloro-3-(1H-pyrazol-4-yl)quinazolin-4(3H)-one; -   (S)-2-(1-aminoethyl)-5-chloro-3-(5-chloro-1H-pyrazol-3-yl)quinazolin-4(3H)-one; -   (S)-2-(1-aminoethyl)-5-chloro-3-(5-fluoro-1H-pyrazol-3-yl)quinazolin-4(3H)-one; -   (S)-2-(1-aminoethyl)-8-chloro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; -   (R)-2-(amino(cyclopropyl)methyl)-5-chloro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; -   (S)-2-(1-aminoethyl)-5-chloro-8-fluoro-3-(1H-pyrazol-4-yl)quinazolin-4(3H)-one; -   (S)-2-(1-aminoethyl)-6,8-difluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; -   (S)-2-(amino(cyclopropyl)methyl)-6,8-difluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; -   (R)-2-(1-aminoethyl)-8-chloro-6-fluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; -   (S)-2-(1-aminoethyl)-3-(1H-pyrazol-3-yl)-5-(trifluoromethyl)quinazolin-4(3H)-one; -   (S)-2-(1-aminoethyl)-5-(difluoromethyl)-3-(1H-pyrazol-4-yl)quinazolin-4(3H)-one; -   (S)-2-(amino(cyclopropyl)methyl)-5-(difluoromethyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; -   (R)-2-(1-aminoethyl)-5-(difluoromethyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; -   (S)-2-(1-aminoethyl)-8-chloro-6-fluoro-3-(1H-pyrazol-4-yl)quinazolin-4(3H)-one; -   (S)-2-(1-aminopropyl)-8-chloro-6-fluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; -   (S)-2-(amino(cyclopropyl)methyl)-8-chloro-6-fluoro-3-(1H-pyrazol-4-yl)quinazolin-4(3H)-one; -   (S)-3-(5-amino-1H-pyrazol-3-yl)-2-(1-aminoethyl)-5-chloroquinazolin-4(3H)-one; -   (S)-2-(amino(cyclopropyl)methyl)-3-(4-methyl-1H-pyrazol-3-yl)-4-oxo-3,4-dihydroquinazoline-8-carbonitrile; -   (S)-2-(1-aminoethyl)-3-(1H-pyrazol-4-yl)-5-(trifluoromethyl)quinazolin-4(3H)-one; -   (S)-2-(1-aminoethyl)-5-chloro-3-(3-methyl-1H-pyrazol-4-yl)quinazolin-4(3H)-one; -   (S)-2-(amino(cyclopropyl)methyl)-3-(1H-pyrazol-3-yl)-5-(trifluoromethyl)quinazolin-4(3H)-one; -   (S)-2-(1-aminoethyl)-5,8-dichloro-3-(3-methyl-1H-pyrazol-4-yl)quinazolin-4(3H)-one; -   (S)-2-(1-aminoethyl)-8-chloro-5-(difluoromethyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; -   (S)-2-(1-aminoethyl)-8-chloro-5-methyl-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; -   (S)-2-(amino(cyclopropyl)methyl)-8-chloro-6-fluoro-3-(3-methyl-1H-pyrazol-4-yl)quinazolin-4(3H)-one; -   (S)-2-(1-aminoethyl)-5,7-difluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; -   (S)-2-(1-aminoethyl)-5-chloro-7-fluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; -   (S)-2-(1-aminoethyl)-6-chloro-5-(difluoromethyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; -   (S)-2-(1-aminoethyl)-7,8-difluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; -   (S)-2-(1-aminopropyl)-5-cyclopropyl-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; -   (S)-2-(amino(cyclopropyl)methyl)-5-chloro-3-(4-methyl-1H-pyrazol-3-yl)quinazolin-4(3H)-one; -   (S)-2-(amino(cyclopropyl)methyl)-5-chloro-7-fluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; -   (S)-2-(1-aminobutyl)-5,8-dichloro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; -   (S)-2-(1-aminobutyl)-5,8-dichloro-3-(1H-pyrazol-4-yl)quinazolin-4(3H)-one; -   (S)-2-(1-aminobutyl)-5-chloro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; -   (S)-2-(1-aminobutyl)-5-chloro-3-(1H-pyrazol-4-yl)quinazolin-4(3H)-one; -   (S)-2-(1-aminoethyl)-5-chloro-6-fluoro-3-(1-pyrazol-3-yl)quinazolin-4(3H)-one; -   (S)-2-(1-aminoethyl)-5-chloro-6-fluoro-3-(1H-pyrazol-4-yl)quinazolin-4(3H)-one; -   (S)-2-(1-aminopropyl)-8-chloro-6-fluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; -   (S)-2-(amino(cyclopropyl)methyl)-5-chloro-6-fluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; -   (S)-2-(1-aminobutyl)-5-chloro-6-fluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; -   (S)-2-(1-aminoethyl)-3-(4-bromo-1H-pyrazol-3-yl)-8-chloro-6-fluoroquinazolin-4(3H)-one; -   (S)-2-(1-aminoethyl)-8-chloro-6-fluoro-3-(1H-pyrazol-4-yl)quinazolin-4(3H)-one; -   (S)-2-(amino(cyclopropyl)methyl)-8-chloro-6-fluoro-3-(1H-pyrazol-4-yl)quinazolin-4(3H)-one; -   (S)-2-(1-aminoethyl)-6-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazoline-8-carbonitrile; -   (S)-2-(amino(cyclopropyl)methyl)-6-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazoline-8-carbonitrile; -   (S)-2-(1-aminoethyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; -   (S)-2-(1-aminoethyl)-5,8-dichloro-3-(1H-imidazol-4-yl)quinazolin-4(3H)-one; -   (S)-2-(1-aminoethyl)-5-chloro-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)quinazolin-4(3H)-one.     ES/MS 420.1 (M+H⁺); -   (S)-2-(amino(cyclopropyl)methyl)-5-chloro-3-(1H-imidazol-4-yl)quinazolin-4(3H)-one;     and -   (S)-2-(1-aminoethyl)-5-chloro-3-(1H-pyrrol-2-yl)quinazolin-4(3H)-one.

C. Preparation of a compound of formula (3) where n is 2, R¹ is chloro, R¹ is fluoro, Z is N, Y is CH, X is C and the attachment point with the quinazolinone, m′ is 0, R⁵ is hydrogen, and R³ is cyclopropyl

To a solution of(S)-tert-butyl ((8-chloro-6-fluoro-4-oxo-3-(1-trityl-1H-imidazol-4-yl)-3,4-dihydroquinazolin-2-yl)(cyclopropyl)methyl)carbamate (638 mg, 0.94 mmol) in DCM (5 mL) were added triethylsilane (0.75 mL, 5 mmol) and TFA (1.4 mL, 19 mmol). The mixture was allowed to stir at ambient temperature until LCMS indicated completion, at which point the reaction was concentrated in vacuo. The resulting residue was suspended in water, washed with toluene, frozen and lyophilized to provide (S)-2-(amino(cyclopropyl)methyl)-8-chloro-6-fluoro-3-(1H-imidazol-4-yl)quinazolin-4(3H)-one, ES/MS 334.1 (M+H⁺).

D. Preparation of the below compounds of formula (3) using the methods in Example 3C and Reaction Theme 1:

-   (S)-2-(1-aminobutyl)-5-chloro-3-(1H-imidazol-4-yl)quinazolin-4(3H)-one.     ES/MS 318.1 (M+H⁺); and -   (S)-2-(1-aminoethyl)-8-chloro-6-fluoro-3-(1H-imidazol-4-yl)quinazolin-4(3H)-one.     ES/MS 308.0 (M+H⁺).

Example 4 Preparation of Compounds of Formula (I)

A. Preparation of a compound of formula (I) where X is CH, Y is N, Z is C and the attachment point with the quinazolinone, A is a single bond, n is 1, R¹ is chloro, m′ is 0, R³ is CH₂CH₃, R⁵ is hydrogen, and R⁴ is 2,6-diamino-5-cyanopyrimidin-4-yl

2-Propanol (3 mL) was added to (S)-2-(1-aminopropyl)-5-chloro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one 2,2,2-trifluoroacetic acid salt (0.25 mmol) and the resulting solution was transferred to a vial containing 2,4-diamino-6-chloropyrimidine-5-carbonitrile (42 mg, 0.25 mmol). Diisopropylethylamine (0.25 mL, 1.5 mmol) was added to the suspension and the reaction mixture was heated to 130° C. for 14 hours in the microwave. The reaction was cooled to room temperature and concentrated. A DMSO solution of the crude mixture was then purified by HPLC eluting with 5%-95% water/acetonitrile (0.1% v/v trifluoroacetic acid). The appropriate fractions were pooled and lyophilized to afford (S)-2,4-diamino-6-((1-(5-chloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile (Compound 1). ¹H NMR (400 MHz, DMSO) δ 13.21 (br s, 1H), 7.92 (d, J=2.4 Hz, 1H), 7.80 (dd, J=8.3, 7.8 Hz, 1H), 7.64-7.57 (m, 2H), 6.58 (d, J=2.4 Hz, 1H), 4.69-4.62 (m, 1H), 2.05-1.93 (m, 1H), 1.85-1.75 (m, 1H), 0.75 (t, J=7.3 Hz, 3H). ES/MS 437.1 (M+H⁺).

B. Preparation of the below compounds of formula (1) using the methods described in Example 4A and Reaction Theme 1:

-   (S)-4-amino-6-((1-(5-chloro-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile     (Compound 2): 1H NMR (400 MHz, DMSO) δ 8.04 (s, 1H), 7.84 (s, 2H),     7.75 (d, J=8 Hz, 2H), 7.60 (dd, J=8.4, 1.2 Hz, 1H), 7.57 (dd, J=6.4,     1.2 Hz, 1H), 7.45 (bs, 2H), 4.94 (m, 1H), 1.38 (d, J=6.8 Hz, 3H).     ES/MS 408.1 (M+H⁺); -   (S)-4-amino-6-((1-(5-chloro-3-(4-methyl-1H-pyrazol-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile     (Compound 3): 1H NMR (400 MHz, DMSO) δ 12.82 (bs, 1H), 7.81 (s, 1H),     7.71 (t, J=8 Hz, 1H), 7.61-7.57 (m, 2H), 7.57-7.53 (m, 2H), 7.21 (m,     2H), 4.80 (app pent, J=7 Hz, 1H), 1.87 (s, 3H), 1.45 (d, J=7 Hz,     3H). ES/MS 422.1 (M+H⁺); -   (S)-4-amino-6-((1-(5-chloro-3-(5-isobutyl-1H-pyrazol-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile     (Compound 4): 1H NMR (400 MHz, DMSO) δ 12.98 (s, 1H), 7.87 (s, 1H),     7.73 (t, J=8 Hz, 1H), 7.57 (dd, J=8, 1 Hz, 1H), 7.53 (dd, J=8, 1 Hz,     1H), 7.44 (d, J=6 Hz, 1H), 7.21 (s, 1H), 4.80 (app quintet, J=7 Hz,     1H), 2.14 (m, 2H), 1.79 (m, 1H), 1.35 (d, J=7 Hz, 3H), 1.01 (d, J=6     Hz, 6H), 464.1. ES/MS 422.1 (M+H⁺); -   (S)-4-amino-6-((1-(5-chloro-3-(5-cyclopropyl-1H-pyrazol-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile     (Compound 5): 1H NMR (400 MHz, DMSO) δ 12.82 (bs, 1H), 7.81 (s, 1H),     7.71 (t, J=8 Hz, 1H), 7.61-7.57 (m, 2H), 7.57-7.53 (m, 2H), 7.21 (m,     2H), 4.80 (app pent, J=7 Hz, 1H), 1.87 (s, 3H), 1.45 (d, J=7 Hz,     3H). ES/MS 422.1 (M+H⁺); -   (S)-4-amino-6-((1-(5-chloro-4-oxo-3-(5-(trifluoromethyl)-1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile     (Compound 6): 1H NMR (400 MHz, DMSO) δ 7.52 (d, J=2 Hz, 1H), 7.20     (t, J=8 Hz, 1H), 6.74 (d, J=8 Hz, 1H), 6.67 (d, J=8 Hz, 1H), 6.67     (m, 1H), 5.68 (s, 1H), 4.28 (m, 1H), 1.50 (d, J=6 Hz, 3H). ES/MS     476.1 (M+H⁺); -   (S)-4-amino-6-((1-(5-chloro-3-(5-methyl-1H-pyrazol-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile     (Compound 7): 1H NMR (400 MHz, DMSO) δ 12.77 (s, 1H), 7.92 (s, 1H),     7.75 (t, J=8 Hz, 1H), 7.58 (dd, dd, J=8, 1 Hz, 1H), 7.54 (dd, J=8, 1     Hz, 1H), 7.41 (d, J=6 Hz, 1H), 7.25 (s, 1H), 6.09 (s, 1H), 4.93 (app     pent, J=7 Hz, 1H), 2.21 (s, 3H), 1.37 (d, J=7 Hz, 3H). ES/MS 422.1     (M+H⁺); -   (S)-5-chloro-3-(5-methyl-1H-pyrazol-3-yl)-2-(1-(thiazolo[5,4-d]pyrimidin-7-ylamino)ethyl)quinazolin-4(3H)-one     (Compound 8): 1H NMR (400 MHz, DMSO) δ 9.24 (s, 1H), 8.32 (d, J=7     Hz, 1H), 8.30 (s, 1H), 7.68 (t, J=8 Hz, 1H), 7.53 (d, J=8 Hz, 1H),     7.49 (d, J=8 Hz, 1H), 6.08 (s, 1H), 5.00 (app pent, J=7 Hz, 1H),     2.10 (s, 3H), 1.44 (d, J=7 Hz, 3H). ES/MS 439.1 (M+H⁺); -   (S)-5-chloro-2-(1-(furo[2,3-d]pyrimidin-4-ylamino)ethyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one     (Compound 9). ¹H NMR (400 MHz, DMSO) δ 8.41 (d, J=6.7 Hz, 1H), 8.36     (br s, 1H), 8.18 (s, 1H), 7.88 (d, J=2.3 Hz, 1H), 7.80 (d, J=2.4 Hz,     1H), 7.77-7.65 (m, 1H), 7.58-7.54 (m, 2H), 7.14 (d, J=2.4 Hz, 1H),     6.51 (d, J=2.6 Hz, 1H), 4.84 (p, J=6.8 Hz, 1H), 1.50 (d, J=6.9 Hz,     3H). ES/MS 408.1 (M+H⁺); -   (S)-2-(cyclopropyl((2,6-diamino-5-chloropyrimidin-4-yl)amino)methyl)-5-fluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one     (Compound 10). ¹H NMR (400 MHz, DMSO) δ 13.18 (br s, 1H), 7.95-7.83     (m, 2H), 7.58 (dd, J=8.3, 1.0 Hz, 1H), 7.55-7.42 (m, 3H), 7.37 (ddd,     J=10.9, 8.2, 1.0 Hz, 1H), 6.37 (d, J=2.4 Hz, 1H), 4.72 (t, J=7.7 Hz,     1H), 1.42-1.32 (m, 1H), 0.52-0.34 (m, 3H), 0.21-0.14 (m, 1H). ES/MS     442.1 (M+H⁺); -   (S)-2-(cyclopropyl((2,6-diamino-5-chloropyrimidin-4-yl)amino)methyl)-5,8-difluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one     (Compound 11). ¹H NMR (400 MHz, DMSO) δ 13.20 (br s, 1H), 7.86 (d,     J=2.5 Hz, 1H), 7.82 (dt, J=9.4, 4.7 Hz, 1H), 7.52-7.34 (m, 4H), 7.29     (br s, 3H), 6.37 (d, J=2.3 Hz, 1H), 4.73 (t, J=7.7 Hz, 1H),     1.45-1.31 (m, 1H), 0.54-0.35 (m, 3H), 0.21-0.14 (m, 1H). ES/MS 460.1     (M+H⁺); -   (S)-2-(cyclopropyl((2,6-diamino-5-chloropyrimidin-4-yl)amino)methyl)-8-fluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one     (Compound 12). ¹H NMR (400 MHz, DMSO) δ 13.20 (br s, 1H), 7.99-7.93     (m, 1H), 7.86 (d, J=2.4 Hz, 1H), 7.80 (ddd, J=10.5, 8.1, 1.4 Hz,     1H), 7.60 (td, J=8.1, 4.7 Hz, 1H), 7.47 (br s, 3H), 7.31 (br s, 2H),     6.38 (d, J=2.3 Hz, 1H), 4.78 (t, J=7.7 Hz, 1H), 1.45-1.33 (m, 1H),     0.53-0.36 (m, 3H), 0.21-0.14 (m, 1H). ES/MS 442.1 (M+H⁺); -   (S)-8-chloro-2-(cyclopropyl((2,6-diamino-5-chloropyrimidin-4-yl)amino)methyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one     (Compound 13). ¹H NMR (400 MHz, DMSO) δ 13.24 (br s, 1H), 8.13-8.07     (m, 2H), 7.91 (d, J=2.4 Hz, 1H), 7.59 (t, J=7.9 Hz, 1H), 7.53-7.19     (m, 4H), 6.42 (d, J=2.3 Hz, 1H), 4.93 (dd, J=7.7, 6.6 Hz, 1H),     1.45-1.33 (m, 1H), 0.50-0.36 (m, 3H), 0.21-0.14 (m, 1H). ES/MS 458.1     (M+H⁺); -   (S)-5-chloro-3-(5-chloro-1H-pyrazol-3-yl)-2-(cyclopropyl((2,6-diamino-5-chloropyrimidin-4-yl)amino)methyl)quinazolin-4(3H)-one     (Compound 14). ¹H NMR (400 MHz, DMSO) δ 7.84 (t, J=8.0 Hz, 1H), 7.72     (dd, J=8.2, 1.2 Hz, 1H), 7.66 (d, J=7.7 Hz, 1H), 7.59 (br s, 1H),     7.50 (br s, 2H), 7.37 (br s, 2H), 6.39 (br s, 1H), 4.68 (br s, 1H),     1.50 (br s, 1H), 0.62-0.38 (m, 3H), 0.17 (br s, 1H). ES/MS 492.1     (M+H⁺); -   (S)-2,4-diamino-6-((1-(5-chloro-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile     (Compound 15). ¹H NMR (400 MHz, DMSO) δ 7.89 (br s, 2H), 7.82-7.74     (m, 1H), 7.62-7.57 (m, 2H), 4.91 (p, J=6.7 Hz, 1H), 1.36 (d, J=6.7     Hz, 3H). ES/MS 423.1 (M+H⁺); -   (S)-2,4-diamino-6-((1-(5-chloro-4-oxo-3-(1H-pyrazoyl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile     (Compound 16). ¹H NMR (400 MHz, DMSO) δ 13.20 (br s, 1H), 7.91 (d,     J=2.4 Hz, 1H), 7.84-7.77 (m, 1H), 7.65-7.59 (m, 2H), 6.55-6.52 (m,     1H), 4.85-4.75 (m, 1H), 1.41 (d, J=6.7 Hz, 3H). ES/MS 423.1 (M+H⁺); -   (S)-2,4-diamino-6-(((5-chloro-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazolin-2-yl)(cyclopropyl)methyl)amino)pyrimidine-5-carbonitrile     (Compound 17). ¹H NMR (400 MHz, DMSO) δ 7.87 (br s 2H), 7.83-7.70     (m, 3H), 7.70-7.56 (m, 2H), 4.80 (t, J=7.5 Hz, 1H), 1.45-1.34 (m,     1H), 0.53-0.36 (m, 3H), 0.18-0.09 (m, 1H). ES/MS 449.1 (M+H⁺); -   (S)-2,4-diamino-6-(((5-chloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)(cyclopropyl)methyl)amino)pyrimidine-5-carbonitrile     (Compound 18). ¹H NMR (400 MHz, DMSO) δ 13.15 (br s, 1H), 7.90-7.74     (m, 2H), 7.69-7.61 (m, 2H), 6.38 (d, J=2.3 Hz, 1H), 4.72 (t. J=7.6     Hz, 1H), 1.47-1.37 (m, 1H), 0.53-0.36 (m, 3H), 0.24-0.14 (m, 1H).     ES/MS 449.1 (M+H⁺); -   (S)-5-chloro-2-(cyclopropyl((2,6-diamino-5-chloropyrimidin-4-yl)amino)methyl)-3-(1H-pyrazol-4-yl)quinazolin-4(3H)-one     (Compound 19). ¹H NMR (400 MHz, DMSO) δ 7.84-7.70 (m, 2H), 7.68 (dd,     J=8.2, 1.2 Hz, 1H), 7.61 (dd, J=7.8, 1.2 Hz, 1H), 7.57-7.30 (m, 4H),     4.78 (t, J=7.6 Hz, 1H), 1.45-1.34 (m, 1H), 0.55-0.34 (m, 3H),     0.16-0.08 (m, 1H). ES/MS 458.1 (M+H⁺); -   (S)-5-chloro-2-(cyclopropyl((2,6-diamino-5-chloropyrimidin-4-yl)amino)methyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one     (Compound 20). ¹H NMR (400 MHz, DMSO) δ 13.17 (br s, 1H), 7.86 (d,     J=2.3 Hz, 1H), 7.82 (t, J=8.0 Hz, 1H), 7.70 (dd, J=8.2, 1.2 Hz, 1H),     7.63 (dd, J=7.8, 1.2 Hz, 1H), 7.49 (br s, 3H), 7.35 (br s, 2H), 6.38     (d, J=2.3 Hz, 1H), 4.71 (t, J=7.7 Hz, 1H), 1.42-1.32 (m, 1H),     0.53-0.37 (m, 3H), 0.22-0.13 (m, 1H). ES/MS 458.1 (M+H⁺); -   (S)-2,4-diamino-6-((1-(5-chloro-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile     (Compound 21). ¹H NMR (400 MHz, DMSO) δ 7.93 (br s, 2H), 7.77 (dd,     J=8.4, 7.6 Hz, 1H), 7.60-7.56 (m, 2H), 4.78 (td, J=7.7, 4.2 Hz, 1H),     1.93-1.72 (m, 2H), 0.72 (t, J=7.3 Hz, 3H). ES/MS 437.1 (M+H⁺); -   (S)-4-amino-6-((1-(5-chloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile     (Compound 22). ¹H NMR (400 MHz, DMSO) δ 13.14 (bs, 1H), 7.93 (s,     1H), 7.87 (d, J=2 Hz, 1H), 7.75 (t, J=8 Hz, 1H), 7.58 (dd, J=8, 1     Hz), 7.54 (dd, J=8, 1 Hz, 1H), 7.43 (d, J=7 Hz, 1H), 7.26 (s, 2H),     6.40 (d, J=2 Hz, 1H), 4.82 (app pent, J=7 Hz, 1H), 1.36 (d, J=7 Hz,     3H). ES/MS 408.1 (M+H⁺); -   (S)-2,4-diamino-6-(2-(5-chloro-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazolin-2-yl)pyrrolidin-1-yl)pyrimidine-5-carbonitrile     (Compound 23). ¹H NMR (400 MHz, DMSO) δ 8.06 (br s, 2H), 8.00 (br s,     1H), 7.71 (t, J=8.0 Hz, 1H), 7.53 (td, J=8.3, 1.1 Hz, 1H), 4.96-4.87     (m, 1H), 4.16-4.04 (m, 1H), 4.01-3.90 (m, 1H), 2.26-2.02 (m, 2H),     2.06-1.85 (m, 2H). ES/MS 449.1 (M+H⁺); -   (S)-2,4-diamino-6-(2-(5-chloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)pyrrolidin-1-yl)pyrimidine-5-carbonitrile     (Compound 24). ¹H NMR (400 MHz, DMSO) δ 13.26 (br s, 1H), 7.96 (d,     J=2.3 Hz, 1H), 7.72 (t, J=8.0 Hz, 1H), 7.56-7.51 (m, 2H), 6.79 (br     s, 1H), 4.61 (br s, 1H), 4.07-3.96 (m, 1H), 3.94-3.86 (m, 1H),     2.24-2.04 (m, 2H), 1.97 (d, J=13.6 Hz, 2H). ES/MS 449.1 (M+H⁺); -   (S)-5-chloro-2-(cyclopropyl(thiazolo[5,4-d]pyrimidin-7-ylamino)methyl)-3-(1H-pyrazol-4-yl)quinazolin-4(3H)-one     (Compound 25). ¹H NMR (400 MHz, DMSO) δ 9.32 (s, 1H), 8.38 (s, 1H),     8.23 (d, J=7.3 Hz, 1H), 7.82 (br s, 2H), 7.76 (t, J=7.8 Hz, 1H),     7.64 (dd, J=8.2, 1.2 Hz, 1H), 7.57 (dd, J=7.8, 1.2 Hz, 1H), 4.87 (t,     J=7.6 Hz, 1H), 1.55-1.45 (m, 1H), 0.56-0.46 (m, 2H), 0.43-0.34 (m,     1H), 0.27-0.20 (m, 1H). ES/MS 451.1 (M+H⁺); -   (S)-5-chloro-2-(cyclopropyl(thiazolo[5,4-d]pyrimidin-7-ylamino)methyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one     (Compound 26). ¹H NMR (400 MHz, DMSO) δ 9.31 (s, 1H), 8.34 (s, 1H),     8.16 (d, J=7.4 Hz, 1H), 7.82-7.77 (m, 2H), 7.68 (dd, J=8.2, 1.2 Hz,     1H), 7.60 (dd, J=7.8, 1.2 Hz, 1H), 6.40 (d, J=2.3 Hz, 1H), 4.75 (t,     J=7.7 Hz, 1H), 1.59-1.49 (m, 1H), 0.52-0.44 (m, 2H), 0.42-0.33 (m,     2H). ES/MS 451.1 (M+H⁺); -   (S)-2-amino-4-(((5-chloro-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazolin-2-yl)(cyclopropyl)methyl)amino)-6-methylpyrimidine-5-carbonitrile     (Compound 27). ¹H NMR (400 MHz, DMSO) δ 7.83-7.77 (m, 2H), 7.63 (dd,     J=8.2, 1.2 Hz, 1H), 7.60 (dd, J=7.8, 1.2 Hz, 1H), 4.81 (t, J=7.5 Hz,     1H), 2.32 (s, 3H), 1.45-1.35 (m, 1H), 0.53-0.35 (m, 3H), 0.16-0.08     (m, 1H). ES/MS 448.1 (M+H⁺); -   (S)-2-amino-4-(((5-chloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)(cyclopropyl)methyl)amino)-6-methylpyrimidine-5-carbonitrile     (Compound 28). ¹H NMR (400 MHz, DMSO) δ 13.11 (br s, 1H), 7.87-7.79     (m, 2H), 7.67 (dd, J=8.2, 1.2 Hz, 1H), 7.62 (dd, J=7.8, 1.2 Hz, 1H),     6.38 (d, J=2.3 Hz, 1H), 4.73 (t, J=7.6 Hz, 1H), 2.30 (s, 3H),     1.47-1.37 (m, 1H), 0.53-0.37 (m, 3H), 0.24-0.15 (m, 1H). ES/MS 448.1     (M+H⁺); -   (S)-2,4-diamino-6-(((8-chloro-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazolin-2-yl)(cyclopropyl)methyl)amino)pyrimidine-5-carbonitrile     (Compound 29). ¹H NMR (400 MHz, DMSO) δ 8.05 (dd, J=8.0, 1.4 Hz,     1H), 8.01 (dd, J=7.8, 1.4 Hz, 1H), 7.80 (br s, 2H), 7.52 (t, J=7.9     Hz, 1H), 4.99 (t, J=7.2 Hz, 1H), 1.37-1.27 (m, 1H), 0.47-0.23 (m,     3H), 0.18-0.08 (m, 1H). ES/MS 449.1 (M+H⁺); -   (S)-2,4-diamino-6-(((8-chloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)(cyclopropyl)methyl)amino)pyrimidine-5-carbonitrile     (Compound 30). ¹H NMR (400 MHz, DMSO) δ 13.18 (br s, 1H), 8.07 (dd,     J=7.9, 1.4 Hz, 1H), 8.03 (dd, J=7.9, 1.4 Hz, 1H), 7.86 (d, J=2.4 Hz,     1H), 7.54 (t, J=7.9 Hz, 1H), 6.39 (d, J=2.3 Hz, 1H), 4.94-4.88 (m,     1H), 1.44-1.34 (m, 1H), 0.46-0.32 (m, 3H), 0.20-0.10 (m, 1H). ES/MS     449.1 (M+H⁺); -   (S)-2,4-diamino-6-((cyclopropyl(5,8-dichloro-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazolin-2-yl)methyl)amino)pyrimidine-5-carbonitrile     (Compound 31). ¹H NMR (400 MHz, DMSO) δ 7.96 (d, J=8.6 Hz, 1H), 7.78     (br s, 2H), 7.56 (d, J=8.5 Hz, 1H), 4.94 (t, J=7.2 Hz, 1H),     1.36-1.26 (m, 1H), 0.46-0.28 (m, 3H), 0.16-0.09 (m, 1H). ES/MS 483.1     (M+H⁺); -   (S)-2,4-diamino-6-((cyclopropyl(5,8-dichloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)methyl)amino)pyrimidine-5-carbonitrile     (Compound 32). ¹H NMR (400 MHz, DMSO) δ 13.18 (br s, 1H), 7.97 (d,     J=8.6 Hz, 1H), 7.86 (br s, 1H), 7.58 (d, J=8.6 Hz, 1H), 6.39 (br s,     1H), 4.87 (t, J=7.1 Hz, 1H), 1.40-1.30 (m, 1H), 0.44-0.32 (m, 3H),     0.18-0.11 (m, 1H). ES/MS 483.1 (M+H⁺); -   (S)-2,4-diamino-6-((1-(8-methyl-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile     (Compound 33). ¹H NMR (400 MHz, DMSO) δ 7.96-7.86 (m, 4H), 7.72-7.68     (m, 1H), 7.44-7.39 (m, 1H), 4.94 (td, J=7.1, 4.2 Hz, 1H), 2.57 (s,     3H), 1.93-1.83 (m, 1H), 1.75-1.63 (m, 1H), 0.70 (t, J=7.3 Hz, 3H).     ES/MS 417.1 (M+H⁺); -   (S)-2,4-diamino-6-((1-(8-methyl-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile     (Compound 34). ¹H NMR (400 MHz, DMSO) δ 13.19 (br s, 1H), 7.97-7.88     (m, 2H), 7.77-7.67 (m, 2H), 7.61-7.52 (m, 1H), 7.44 (t, J=7.6 Hz,     1H), 6.49 (d, J=2.3 Hz, 1H), 4.86 (td, J=6.8, 4.4 Hz, 1H), 2.58 (s,     3H), 2.05-1.91 (m, 1H), 1.77-1.65 (m, 1H), 0.72 (t, J=7.3 Hz, 3H).     ES/MS 417.1 (M+H⁺); -   (S)-2,4-diamino-6-((1-(5-fluoro-8-methyl-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile     (Compound 35). ¹H NMR (400 MHz, DMSO) δ 7.87 (br s, 2H), 7.68 (ddd,     J=8.3, 5.5, 1.0 Hz, 1H), 7.50 (br s, 2H), 7.19 (dd, J=11.0, 8.3 Hz,     1H), 4.90 (td, J=7.2, 4.1 Hz, 1H), 2.49 (s, 3H), 1.92-1.82 (m, 1H),     1.75-1.62 (m, 1H), 0.70 (t, J=7.3 Hz, 3H). ES/MS 435.2 (M+H⁺); -   (S)-2,4-diamino-6-((1-(5-fluoro-8-methyl-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile     (Compound 36). ¹H NMR (400 MHz, DMSO) δ 13.19 (br s, 1H), 7.90 (dd,     J=2.4, 0.8 Hz, 1H), 7.70 (dd, J=8.4, 5.4 Hz, 1H), 7.63 (br s, 2H),     7.45 (br s, J=8.3 Hz, 1H), 7.21 (dd, J=10.9, 8.3 Hz, 1H), 6.49 (dd,     J=2.4, 0.8 Hz, 1H), 4.81 (td, J=7.1, 4.4 Hz, 1H), 2.51 (s, 3H), 1.96     (ddt, J=14.4, 11.6, 7.1 Hz, 1H), 1.71 (dp, J=14.5, 7.2 Hz, 1H), 0.72     (t, J=7.3 Hz, 3H). ES/MS 435.2 (M+H⁺); -   (S)-5,8-dichloro-2-(cyclopropyl(thiazolo[5,4-d]pyrimidin-7-ylamino)methyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one     (Compound 37). ¹H NMR (400 MHz, DMSO) δ 9.27 (s, 1H), 8.30 (s, 1H),     8.02 (d, J=7.6 Hz, 1H), 7.96 (d, J=8.5 Hz, 1H), 7.75 (d, J=2.4 Hz,     1H), 7.56 (d, J=8.5 Hz, 1H), 6.31 (d, J=2.4 Hz, 1H), 4.90 (t, J=7.6     Hz, 1H), 1.58-1.47 (m, 1H), 0.51-0.35 (m, 3H), 0.32-0.24 (m, 1H).     ES/MS 485.1 (M+H⁺); -   (S)-5,8-dichloro-2-(cyclopropyl(thiazolo[5,4-d]pyrimidin-7-ylamino)methyl)-3-(1H-pyrazol-4-yl)quinazolin-4(3H)-one     (Compound 38). ¹H NMR (400 MHz, DMSO) δ 9.28 (s, 1H), 8.32 (s, 1H),     8.07 (d, J=7.5 Hz, 1H), 7.94 (dd, J=8.5, 0.7 Hz, 1H), 7.74 (br s,     2H), 7.54 (dd, J=8.5, 0.7 Hz, 1H), 5.00 (t, J=7.5 Hz, 1H), 1.54-1.45     (m 1H), 0.52-0.36 (m, 4H), 0.27-0.19 (m, 1H). ES/MS 485.1 (M+H⁺); -   (S)-5,8-dichloro-3-(1H-pyrazol-4-yl)-2-(1-(thiazolo[5,4-d]pyrimidin-7-ylamino)propyl)quinazolin-4(3H)-one     (Compound 39). ¹H NMR (400 MHz, DMSO) δ 9.28 (d, J=0.8 Hz, 1H), 8.37     (d, J=0.8 Hz, 1H), 8.33 (d, J=7.3 Hz, 1H), 7.90 (dd, J=8.6, 0.9 Hz,     1H), 7.81 (br s, 2H), 7.51 (dd, J=8.5, 0.8 Hz, 1H), 5.02 (td, J=7.6,     4.8 Hz, 1H), 2.07-1.94 (m, 1H), 1.93-1.80 (m, 1H), 0.82 (t, J=7.3     Hz, 3H). ES/MS 473.1 (M+H⁺); -   (S)-5,8-dichloro-2-(1-(imidazo[2,1-f][1,2,4]triazin-4-ylamino)propyl)-3-(1H-pyrazol-4-yl)quinazolin-4(3H)-one     (Compound 40). ¹H NMR (400 MHz, DMSO) δ 8.88 (d, J=7.2 Hz, 1H), 8.07     (s, 1H), 8.05 (d, J=1.1 Hz, 1H), 7.91 (d, J=8.5 Hz, 1H), 7.80 (br s,     2H), 7.60 (d, J=1.2 Hz, 1H), 7.52 (d, J=8.5 Hz, 1H), 4.96 (td,     J=7.6, 4.9 Hz, 1H), 2.06-1.95 (m, 1H), 1.93-1.86 (m, 1H), 0.82 (t,     J=7.3 Hz, 3H). ES/MS 456.1 (M+H⁺); -   (S)-5,8-dichloro-3-(1H-pyrazol-4-yl)-2-(1-(pyrido[3,2-d]pyrimidin-4-ylamino)propyl)quinazolin-4(3H)-one     (Compound 41). ¹H NMR (400 MHz, DMSO) δ 13.24 (br s, 1H), 9.31 (br     s, 1H), 8.92 (dt, J=4.4, 1.1 Hz, 1H), 8.62 (s, 1H), 8.15 (dt, J=8.5,     1.2 Hz, 1H), 7.99-7.90 (m, 2H), 7.88 (dd, J=2.4, 0.9 Hz, 1H), 7.57     (dd, J=8.5, 0.9 Hz, 1H), 6.42 (dd, J=2.4, 0.9 Hz, 1H), 5.14 (td,     J=7.6, 4.6 Hz, 1H), 2.16-2.03 (m, 1H), 1.94-1.82 (m, 1H), 0.87-0.77     (t, J=7.3 Hz, 3H). ES/MS 467.1 (M+H⁺); -   (S)-5,8-dichloro-2-(1-((6-chloropyrido[3,2-d]pyrimidin-4-yl)amino)propyl)-3-(1H-pyrazol-4-yl)quinazolin-4(3H)-one     (Compound 42). ¹H NMR (400 MHz, DMSO) δ 9.13 (d, J=7.5 Hz, 1H), 8.61     (s, 1H), 8.19 (d, J=8.8 Hz, 1H), 7.97 (d, J=4.7 Hz, 1H), 7.95 (d,     J=4.5 Hz, 1H), 7.81 (s, 2H), 7.56 (d, J=8.5 Hz, 1H), 5.17 (td,     J=7.4, 4.6 Hz, 1H), 2.13-2.01 (m, 1H), 1.89-1.79 (m, 1H), 0.82 (t,     J=7.3 Hz, 3H). ES/MS 501.1 (M+H⁺); -   (S)-5,8-dichloro-2-(1-(imidazo[2,1-f][1,2,4]triazin-4-ylamino)propyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one     (Compound 43). ¹H NMR (400 MHz, DMSO) δ 8.76 (d, J=7.3 Hz, 1H), 8.05     (d, J=1.1 Hz, 1H), 8.04 (s, 1H), 7.93 (d, J=8.5 Hz, 1H), 7.84 (d,     J=2.4 Hz, 1H), 7.60 (d, J=1.2 Hz, 1H), 7.55 (d, J=8.5 Hz, 1H), 6.38     (d, J=2.4 Hz, 1H), 4.91 (td, J=7.6, 4.8 Hz, 1H), 2.13-2.02 (m, 1H),     1.92-1.83 (m, 1H), 0.81 (t, J=7.3 Hz, 3H). ES/MS 456.1 (M+H⁺); -   (S)-5,8-dichloro-3-(1H-pyrazol-3-yl)-2-(1-(pyrido[3,2-d]pyrimidin-4-ylamino)propyl)quinazolin-4(3H)-one     (Compound 44). ¹H NMR (400 MHz, DMSO) δ 13.24 (br s, 1H), 8.94-8.90     (m, 1H), 8.65-8.60 (m, 1H), 8.15 (d, J=8.6 Hz, 1H), 7.96 (d, J=8.5     Hz, 1H), 7.88 (d, J=2.4 Hz, 1H), 7.57 (d, J=8.5 Hz, 1H), 6.42 (d,     J=2.4 Hz, 1H), 5.17-5.11 (m, 1H), 2.16-2.05 (m, 1H), 1.94-1.82 (m,     1H), 0.82 (t, J=7.3 Hz, 3H). ES/MS 467.1 (M+H⁺); -   (S)-5,8-dichloro-2-(1-((6-chloropyrido[3,2-d]pyrimidin-4-yl)amino)propyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one     (Compound 45). ¹H NMR (400 MHz, DMSO) δ 8.97 (br s, 1H), 8.55 (s,     1H), 8.18 (d, J=8.8 Hz, 1H), 7.97 (d, J=8.5 Hz, 1H), 7.95 (d, J=8.8     Hz, 1H), 7.58 (d, J=8.5 Hz, 1H), 6.41 (d, J=2.4 Hz, 1H), 5.13 (td,     J=7.3, 4.6 Hz, 1H), 2.15-2.04 (m, 1H), 1.86-1.75 (m, 1H), 0.80 (t,     J=7.3 Hz, 3H). ES/MS 501.1 (M+H⁺); -   (S)-5,8-dichloro-3-(1H-pyrazol-3-yl)-2-(1-(thiazolo[5,4-d]pyrimidin-7-ylamino)propyl)quinazolin-4(3H)-one     (Compound 46). ¹H NMR (400 MHz, DMSO) δ 9.28 (s, 1H), 8.33 (s, 1H),     8.22 (d, J=7.5 Hz, 1H), 7.93 (d, J=8.5 Hz, 1H), 7.83 (d, J=2.4 Hz,     1H), 7.54 (d, J=8.5 Hz, 1H), 6.39 (d, J=2.4 Hz, 1H), 5.03-4.93 (m,     1H), 2.11-2.02 (m, 1H), 1.89-1.79 (m, 1H), 0.81 (t, J=7.3 Hz, 3H).     ES/MS 473.1 (M+H⁺); -   (R)-2-(2-(benzyloxy)-1-(thiazolo[5,4-d]pyrimidin-7-ylamino)ethyl)-5-chloro-3-(1H-pyrazol-4-yl)quinazolin-4(3H)-one     (Compound 47). ¹H NMR (400 MHz, DMSO) δ 13.15 (s, 1H), 9.28 (s, 1H),     8.47 (d, J=7.0 Hz, 1H), 8.39 (s, 1H), 7.96 (s, 1H), 7.71 (dd, J=8.4,     7.7 Hz, 1H), 7.58 (s, 1H), 7.57-7.51 (m, 2H), 7.27-7.17 (m, 2H),     7.17-7.11 (m, 2H), 5.30 (q, J=6.4 Hz, 1H), 4.43-4.33 (ABq, 2H), 3.94     (dd, J=10.1, 5.4 Hz, 1H), 3.85 (dd, J=10.1, 7.0 Hz, 1H). ES/MS 531.1     (M+H⁺); -   (R)-2-(2-(benzyloxy)-1-(thiazolo[5,4-d]pyrimidin-7-ylamino)ethyl)-5-chloro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one     (Compound 48). ¹H NMR (400 MHz, DMSO) δ 13.19 (br s, 1H), 9.28 (s,     1H), 8.37-8.29 (m, 2H), 7.85-7.79 (m, 1H), 7.78-7.70 (m, 1H),     7.63-7.55 (m, 2H), 7.26-7.12 (m, 5H), 6.33 (t, J=2.2 Hz, 1H), 5.30     (dt, J=7.5, 5.3 Hz, 1H), 4.42-4.33 (ABq, 2H), 3.98 (dd, J=10.1, 4.7     Hz, 1H), 3.82 (dd, J=10.1, 6.9 Hz, 1H). ES/MS 531.1 (M+H⁺); -   (S)-2,4-diamino-6-((1-(5-chloro-3-(5-(3-methoxypropyl)-1H-pyrazol-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile     (Compound 49). ¹H NMR (400 MHz, DMSO) δ 12.86 (br s, 1H), 7.85-7.62     (m, 6H), 7.57 (ddt, J=9.1, 7.6, 1.3 Hz, 2H), 7.44-7.12 (br s, 3H),     6.24 (s, 1H), 4.74 (q, J=6.9 Hz, 1H), 3.36-3.28 (m, 2H), 3.21 (d,     J=1.0 Hz, 3H), 2.70-2.59 (m, 2H), 2.04-1.92 (m, 1H), 1.82-1.71 (m,     3H), 0.75 (t, J=7.3 Hz, 3H). ES/MS 509.2 (M+H⁺); -   (R)-5-chloro-2-(2-hydroxy-1-(thiazolo[5,4-d]pyrimidin-7-ylamino)ethyl)-3-(1H-pyrazol-4-yl)quinazolin-4(3H)-one     (Compound 50). ¹H NMR (400 MHz, DMSO) δ 9.31 (s, 0.2H), 9.29 (s,     0.8H), 8.41 (s, 0.8H), 8.37 (s, 0.2H), 8.17-8.10 (m, 1H), 7.90-7.83     (m, 2H), 7.69 (t, J=8.0 Hz, 1H), 7.57-7.50 (m, 2H), 5.12-5.05 (m,     1H), 4.42 (d, J=5.0 Hz, 0.4H), 3.86 (dd, J=11.2, 5.5 Hz, 0.8H), 3.75     (dd, J=11.3, 6.2 Hz, 0.8H). ES/MS 441.1 (M+H⁺); -   (R)-5-chloro-2-(2-hydroxy-1-(thiazolo[5,4-d]pyrimidin-7-ylamino)ethyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one     (Compound 51). ¹H NMR (400 MHz, DMSO) δ 9.30 (s, 1H), 8.35 (s, 1H),     8.12 (d, J=7.7 Hz, 0.2H), 8.00 (d, J=7.1 Hz, 0.8H), 7.96 (d, J=2.4     Hz, 0.2H), 7.88 (d, J=2.3 Hz, 0.8H), 7.73 (t, J=8.0 Hz, 1H),     7.61-7.46 (m, 2H), 6.48 (d, J=2.4 Hz, 0.2H), 6.44 (d, J=2.4 Hz,     0.8H), 5.07-4.98 (m, 1H), 4.38 (d, J=5.5 Hz, 0.4H), 3.84 (dd,     J=11.4, 4.5 Hz, 0.8H), 3.75 (dd, J=11.3, 5.6 Hz, 0.8H). ES/MS 441.1     (M+H⁺); -   (S)-2-(1-((9H-purin-6-yl)amino)propyl)-5,8-dichloro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one     (Compound 52). ¹H NMR (400 MHz, DMSO) δ 13.24 (br s, 1H), 8.35 (br     s, 2H), 7.98-7.89 (m, 2H), 7.61-7.56 (m, 1H), 6.50 (br s, 1H),     5.01-4.92 (m, 1H), 2.20-2.07 (m, 1H), 1.91-1.80 (m, 1H), 0.87 (t,     J=7.3 Hz, 3H). ES/MS 456.0 (M+H⁺); -   (S)-5,8-dichloro-2-(1-((2-fluoro-9H-purin-6-yl)amino)propyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one     (Compound 53). ¹H NMR (400 MHz, DMSO) δ 13.25 (br s, 1H), 8.27 (d,     J=7.4 Hz, 1H), 8.18 (s, 1H), 7.96 (d, J=8.5 Hz, 1H), 7.89 (d, J=2.4     Hz, 1H), 7.57 (d, J=8.5 Hz, 1H), 6.41 (d, J=2.4 Hz, 1H), 4.85-4.74     (m, 1H), 2.15-2.00 (m, 1H), 1.92-1.83 (m, 1H), 0.86 (t, J=7.3 Hz,     3H). ES/MS 474.0 (M+H⁺); -   (S)-5,8-dichloro-3-(1H-pyrazol-3-yl)-2-(1-(thieno[2,3-d]pyrimidin-4-ylamino)propyl)quinazolin-4(3H)-one     (Compound 54). ¹H NMR (400 MHz, DMSO) δ 8.42 (d, J=7.3 Hz, 1H), 8.33     (s, 1H), 7.94 (d, J=8.5 Hz, 1H), 7.85 (d, J=2.4 Hz, 1H), 7.81 (d,     J=6.0 Hz, 1H), 7.63 (d, J=5.9 Hz, 1H), 7.56 (d, J=8.5 Hz, 1H), 6.45     (d, J=2.3 Hz, 1H), 4.87 (ddd, J=9.0, 7.1, 4.5 Hz, 1H), 2.21-2.08 (m,     1H), 1.96-1.85 (m, 1H), 0.90 (t, J=7.3 Hz, 3H). ES/MS 472.0 (M+H⁺); -   (S)-5,8-dichloro-2-(1-((2-fluoro-9H-purin-6-yl)amino)propyl)-3-(1H-pyrazol-4-yl)quinazolin-4(3H)-one     (Compound 55). ¹H NMR (400 MHz, DMSO) δ 8.38 (d, J=7.3 Hz, 1H), 8.21     (s, 1H), 7.94 (d, J=8.5 Hz, 1H), 7.82 (s, 2H), 7.55 (d, J=8.5 Hz,     1H), 4.95-4.85 (m, 1H), 2.06-1.96 (m, 1H), 1.93-1.83 (m, 1H), 0.87     (t, J=7.3 Hz, 3H). ES/MS 474.0 (M+H⁺); -   (S)-5,8-dichloro-3-(1H-pyrazol-4-yl)-2-(1-(thieno[2,3-d]pyrimidin-4-ylamino)propyl)quinazolin-4(3H)-one     (Compound 56). ¹H NMR (400 MHz, DMSO) δ 8.43 (d, J=7.2 Hz, 1H), 8.38     (s, 1H), 7.91 (d, J=8.5 Hz, 1H), 7.87 (s, 2H), 7.82 (d, J=6.0 Hz,     1H), 7.63 (d, J=6.0 Hz, 1H), 7.54 (d, J=8.5 Hz, 1H), 4.97-4.90 (m,     1H), 2.12-1.99 (m, 1H), 1.97-1.84 (m, 1H), 0.90 (t, J=7.3 Hz, 3H).     ES/MS 472.0 (M+H⁺); -   (S)-2-(1-((5-bromothieno[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-chloro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one     (Compound 126); -   (S)-2-(1-((9H-purin-6-yl)amino)propyl)-5,8-dichloro-3-(1H-pyrazol-4-yl)quinazolin-4(3H)-one     (Compound 57). ¹H NMR (400 MHz, DMSO) δ 8.71 (br s, 1H), 8.49 (br s,     1H), 8.45 (br s, 1H), 7.96-7.86 (m, 3H), 7.56 (d, J=8.5 Hz, 1H),     5.09-5.00 (m, 1H), 2.14-2.02 (m, 1H), 1.96-1.80 (m, 1H), 0.89 (t,     J=7.3 Hz, 3H). ES/MS 456.0 (M+H⁺); -   (S)-5,8-dichloro-2-(1-((5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)propyl)-3-(1H-pyrazol-4-yl)quinazolin-4(3H)-one     (Compound 58). ¹H NMR (400 MHz, DMSO) δ 8.17 (s, 1H), 7.98 (d, J=8.5     Hz, 1H), 7.88 (s, 2H), 7.58 (d, J=8.5 Hz, 1H), 7.28 (br s, 1H), 7.21     (s, 1H), 5.21 (td, J=7.2, 4.6 Hz, 1H), 2.05-1.97 (m, 1H), 1.82-1.72     (m, 1H), 0.82 (t, J=7.3 Hz, 3H). ES/MS 473.0 (M+H⁺); -   (S)-5,8-dichloro-2-(1-((5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)propyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one     (Compound 59). ¹H NMR (400 MHz, DMSO) δ 13.31 (br s, 1H), 11.67 (br     s, 1H), 8.13 (s, 1H), 8.00 (d, J=8.5 Hz, 1H), 7.94 (d, J=2.4 Hz,     1H), 7.60 (d, J=8.6 Hz, 1H), 7.19 (s, 1H), 6.48 (d, J=2.4 Hz, 1H),     5.21-5.13 (m, 1H), 2.12-1.98 (m, 1H), 1.83-1.68 (m, 1H), 0.81 (t,     J=7.3 Hz, 3H). ES/MS 473.0 (M+H⁺); -   (S)-5-chloro-3-(1H-pyrazol-3-yl)-2-(1-(thieno[2,3-d]pyrimidin-4-ylamino)ethyl)quinazolin-4(3H)-one     (Compound 60). ¹H NMR (400 MHz, DMSO) δ 8.57 (d, J=6.6 Hz, 1H), 8.35     (s, 1H), 7.88 (d, J=2.4 Hz, 1H), 7.78 (d, J=6.0 Hz, 1H), 7.74-7.70     (m, 1H), 7.63 (d, J=6.0 Hz, 1H), 7.57 (s, 1H), 7.55 (s, 1H), 6.52     (d, J=2.3 Hz, 1H), 4.88 (p, J=6.8 Hz, 1H), 1.54 (d, J=6.9 Hz, 3H).     ES/MS 424.1 (M+H⁺); -   (S)-5-chloro-2-(1-(furo[3,2-d]pyrimidin-4-ylamino)ethyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one     (Compound 61). ¹H NMR (400 MHz, DMSO) δ 13.20 (s, 1H), 9.48 (br s,     1H), 8.56 (s, 1H), 8.47 (dt, J=2.1, 1.0 Hz, 1H), 7.89 (d, J=2.4 Hz,     1H), 7.75 (dd, J=8.5, 7.6 Hz, 1H), 7.59 (s, 1H), 7.57 (s, 1H), 7.12     (dd, J=2.0, 1.0 Hz, 1H), 6.54 (d, J=2.3 Hz, 1H), 5.00, 4.90 (m, 1H),     1.55 (d, J=6.8 Hz, 3H). ES/MS 408.1 (M+H⁺); -   (S)-5,8-dichloro-2-(1-(furo[3,2-d]pyrimidin-4-ylamino)propyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one     (Compound 62). ¹H NMR (400 MHz, DMSO) δ 13.20 (br s, 1H), 9.23 (br     s, 1H), 8.51 (s, 1H), 8.46 (d, J=2.2 Hz, 1H), 7.95 (d, J=8.5 Hz,     1H), 7.86 (d, J=2.4 Hz, 1H), 7.58 (d, J=8.5 Hz, 1H), 7.12 (d, J=2.2     Hz, 1H), 6.48 (d, J=2.4 Hz, 1H), 4.93-4.85 (m, 1H), 2.21-2.09 (m,     1H), 2.00-1.88 (m, 1H), 0.88 (t, J=7.2 Hz, 3H). ES/MS 456.0 (M+H⁺); -   (S)-2-amino-4-chloro-6-(((5-chloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)(cyclopropyl)methyl)amino)pyrimidine-5-carbonitrile     (Compound 63). ¹H NMR (400 MHz, DMSO) δ 13.08 (br s, 1H), 7.85-7.78     (m, 2H), 7.67 (dd, J=8.2, 1.2 Hz, 1H), 7.62 (dd, J=7.8, 1.2 Hz, 1H),     7.57 (d, J=7.4 Hz, 1H), 7.29 (br s, 1H), 6.35 (d, J=2.4 Hz, 1H),     4.71 (t, J=7.7 Hz, 1H), 1.48-1.39 (m, 1H), 0.54-0.38 (m, 3H),     0.22-0.13 (m, 1H). ES/MS 468.1 (M+H⁺); -   (S)-5-chloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one     (Compound 64). ¹H NMR (400 MHz, DMSO) δ 13.22 (br s, 1H), 7.91 (d,     J=2.4 Hz, 1H), 7.81 (t, J=8.0 Hz, 1H), 7.71 (d, J=6.8 Hz, 1H), 7.66     (dd, J=8.2, 1.2 Hz, 1H), 7.62 (dd, J=7.8, 1.2 Hz, 1H), 7.52 (br s,     2H), 7.38 (br s, 2H), 6.54 (d, J=2.4 Hz, 1H), 4.79 (p, J=6.7 Hz,     1H), 1.43 (d, J=6.8 Hz, 3H). ES/MS 432.1 (M+H⁺); -   (S)-5-chloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)propyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one     (Compound 65). ¹H NMR (400 MHz, DMSO) δ 13.26 (br s, 1H), 7.94 (d,     J=2.4 Hz, 1H), 7.80 (t, J=8.0 Hz, 1H), 7.66-7.58 (m, 3H), 7.50 (br     s, 2H), 7.30 (br s, 2H), 6.59 (d, J=2.3 Hz, 1H), 4.64 (td, J=7.5,     3.9 Hz, 1H), 2.07-1.94 (m, 1H), 1.89-1.77 (m, 1H), 0.74 (t, J=7.3     Hz, 3H). ES/MS 446.1 (M+H⁺); -   (S)-5,8-dichloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)propyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one     (Compound 66). ¹H NMR (400 MHz, DMSO) δ 13.28 (br s, 1H), 8.01 (d,     J=8.5 Hz, 1H), 7.95 (d, J=2.4 Hz, 1H), 7.61 (d, J=8.5 Hz, 1H), 7.56     (br s, 1H), 7.49 (br s, 1H), 7.34 (br s, 2H), 6.52 (d, J=2.3 Hz,     1H), 4.83 (td, J=7.0, 4.5 Hz, 1H), 2.07-1.95 (m, 1H), 1.83-1.72 (m,     1H), 0.77 (t, J=7.3 Hz, 3H). ES/MS 480.0 (M+H⁺); -   (S)-5-chloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-8-fluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one     (Compound 67). ¹H NMR (400 MHz, DMSO) δ 13.25 (br s, 1H), 7.92 (d,     J=2.3 Hz, 1H), 7.77 (t, J=9.2 Hz, 1H), 7.68 (d, J=6.6 Hz, 1H), 7.62     (dd, J=8.8, 4.5 Hz, 1H), 7.49 (br s, 2H), 7.34 (br s, 2H), 6.53 (d,     J=2.3 Hz, 1H), 4.81 (p, J=6.6 Hz, 1H), 1.44 (d, J=6.7 Hz, 3H). ES/MS     450.1 (M+H⁺); -   (S)-5-chloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)propyl)-8-fluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one     (Compound 68). ¹H NMR (400 MHz, DMSO) δ 13.27 (s, 1H), 7.94 (d,     J=2.4 Hz, 1H), 7.76 (dd, J=9.6, 8.8 Hz, 1H), 7.61 (dd, J=8.8, 4.5     Hz, 1H), 7.53 (br s, 2H), 7.41 (br s, 3H), 7.19 (br s, 2H), 6.58 (d,     J=2.3 Hz, 1H), 4.68-4.61 (m, 1H), 2.06-1.95 (m, 1H), 1.88-1.76 (m,     1H), 0.76 (t, J=7.3 Hz, 3H). ES/MS 464.1 (M+H⁺); -   (S)-5,8-dichloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one     (Compound 69). ¹H NMR (400 MHz, DMSO) δ 13.27 (s, 1H), 8.02 (d,     J=8.6 Hz, 1H), 7.94 (d, J=2.4 Hz, 1H), 7.71 (br s, 1H), 7.62 (d,     J=8.5 Hz, 1H), 7.48 (br s, 2H), 7.41 (br s, 3H), 6.49 (d, J=2.3 Hz,     1H), 4.88 (p, J=6.7 Hz, 1H), 1.43 (d, J=6.7 Hz, 3H). ES/MS 466.0     (M+H⁺); -   (S)-5-chloro-2-(cyclopropyl((2,6-diamino-5-chloropyrimidin-4-yl)amino)methyl)-8-fluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one     (Compound 70). ¹H NMR (400 MHz, DMSO) δ 13.20 (s, 1H), 7.86 (d,     J=2.4 Hz, 1H), 7.79 (dd, J=9.6, 8.8 Hz, 1H), 7.64 (dd, J=8.8, 4.5     Hz, 1H), 7.49 (br s, 5H), 7.34 (br s, 2H), 6.37 (d, J=2.4 Hz, 1H),     4.73 (t, J=7.7 Hz, 1H), 1.45-1.33 (m, 1H), 0.54-0.36 (m, 3H),     0.23-0.15 (m, 1H). ES/MS 476.1 (M+H⁺); -   (S)-5,8-dichloro-2-(cyclopropyl((2,6-diamino-5-chloropyrimidin-4-yl)amino)methyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one     (Compound 71). ¹H NMR (400 MHz, DMSO) δ 13.24 (s, 1H), 8.03 (d,     J=8.6 Hz, 1H), 7.90 (d, J=2.4 Hz, 1H), 7.63 (d, J=8.5 Hz, 11H), 7.51     (br s, 2H), 7.42 (br s, 5H), 6.40 (d, J=2.3 Hz, 1H), 4.88 (t, J=7.2     Hz, 1H), 1.46-1.36 (m, 1H), 0.50-0.37 (m, 3H), 0.21-0.13 (m, 1H).     ES/MS 492.0 (M+H⁺); -   (S)-2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one     (Compound 72). ¹H NMR (400 MHz, DMSO) δ 13.30 (s, 1H), 8.78 (d,     J=2.9 Hz, 1H), 8.08 (s, 1H), 8.01-7.85 (m, 4H), 7.63 (dd, J=7.4, 1.6     Hz, 1H), 7.48-7.29 (m, 2H), 6.52 (d, J=2.3 Hz, 1H), 4.91-4.82 (m,     1H), 1.39 (d, J=6.6 Hz, 3H). ES/MS 502.1 (M+H⁺); -   (S)-4-oxo-3-(1H-pyrazol-3-yl)-2-(1-(thiazolo[5,4-d]pyrimidin-7-ylamino)propyl)-3,4-dihydroquinazoline-5-carbonitrile     (Compound 73). ¹H NMR (400 MHz, DMSO-d₆) δ 13.26 (s, 1H), 9.28 (s,     1H), 8.38 (d, J=7.3 Hz, 1H), 8.33 (s, 1H), 8.02 (dd, J=6.1, 2.6 Hz,     1H), 7.97-7.82 (m, 3H), 6.50 (d, J=2.3 Hz, 1H), 4.87 (td, J=8.2, 4.3     Hz, 1H), 2.13-1.81 (m, 2H), 0.79 (t, J=7.2 Hz, 3H). ES/MS 430.1     (M+H⁺); -   (S)-4-oxo-3-(1H-pyrazol-3-yl)-2-(1-(thiazolo[5,4-d]pyrimidin-7-ylamino)propyl)-3,4-dihydroquinazoline-8-carbonitrile     (Compound 74). ¹H NMR (400 MHz, DMSO-d₆) δ 13.19 (s, 1H), 9.27 (s,     1H), 8.39-8.30 (m, 3H), 8.29 (d, J=7.4 Hz, 1H), 7.82 (dd, J=2.3, 1.4     Hz, 1H), 7.65 (t, J=7.8 Hz, 1H), 6.39 (t, J=2.1 Hz, 1H), 5.05-4.94     (m, 1H), 2.17-1.83 (m, 2H), 0.83 (t, J=7.3 Hz, 3H). ES/MS 430.1     (M+H⁺); -   (S)-2-(1-((2,6-diamino-5-cyanopyrimidin-4-yl)amino)propyl)-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazoline-8-carbonitrile     (Compound 75). ¹H NMR (400 MHz, DMSO-d₆) δ 13.16 (br. s, 1H), 8.37     (d, J=7.8 Hz, 1H), 8.03-7.85 (m, 3H), 7.84 (d, J=2.3 Hz, 1H), 7.68     (t, J=7.8 Hz, 1H), 7.64-7.23 (m, 2H), 6.45 (d, J=2.3 Hz, 1H), 4.85     (td, J=7.5, 5.3 Hz, 1H), 2.13-1.97 (m, 1H), 1.92-1.75 (m, 1H), 0.81     (t, J=7.3 Hz, 3H). ES/MS 428.1 (M+H⁺); -   (S)-2-(1-((2-amino-5-cyano-6-methylpyrimidin-4-yl)amino)propyl)-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazoline-8-carbonitrile     (Compound 76). ¹H NMR (400 MHz, DMSO-d₆) δ 3.14 (s, 1H), 8.37 (d,     J=7.8 Hz, 1H), 8.20 (s, 1H), 7.81 (d, J=2.4 Hz, 1H), 7.74 (s, 2H),     7.68 (t, J=7.8 Hz, 1H), 6.43 (d, J=2.3 Hz, 1H), 4.89 (td, J=7.4, 5.4     Hz, 1H), 2.33 (s, 3H), 2.19-2.01 (m, 1H), 1.97-1.77 (m, 1H), 0.83     (t, J=7.3 Hz, 3H). ES/MS 427.2 (M+H⁺); -   (S)-3-(4-bromo-1H-pyrazol-3-yl)-5-chloro-2-(1-(thiazolo[5,4-d]pyrimidin-7-ylamino)propyl)quinazolin-4(3H)-one     (Compound 77). ¹H NMR (400 MHz, DMSO-d₆) δ 13.65 (br. s, 1H),     9.30-9.24 (m, 1H), 8.47 (d, J=7.7 Hz, 1H), 8.33-8.23 (m, 1H),     8.23-8.10 (m, 2H), 7.83-7.69 (m, 1H), 7.69-7.53 (m, 2H), 5.21-4.69     (m, 1H), 2.27-1.69 (m, 2H), 0.88-0.74 (m, 3H). ES/MS 517.0 (M+H⁺); -   (S)-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)propyl)-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazoline-8-carbonitrile     (Compound 78). ¹H NMR (400 MHz, DMSO-d₆) δ 13.26 (s, 1H), 8.54-8.23     (m, 2H), 7.91 (d, J=2.4 Hz, 1H), 7.69 (t, J=7.8 Hz, 1H), 7.63-7.09     (m, 4H), 6.50 (d, J=2.3 Hz, 1H), 4.82 (td, J=7.1, 4.5 Hz, 1H),     2.09-1.93 (m, 1H), 1.85-1.67 (m, 1H), 0.74 (t, J=7.3 Hz, 3H). ES/MS     437.1 (M+H⁺); -   (S)-2-(1-((6-amino-3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)propyl)-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazoline-5-carbonitrile     (Compound 79). ¹H NMR (400 MHz, DMSO-d₆) δ 13.30 (br. s, 1H), 8.11     (dd, J=8.1, 1.3 Hz, 1H), 8.05 (dd, J=7.5, 1.3 Hz, 1H), 8.01-7.90 (m,     3H), 7.63 (br. s, 1H), 7.01 (br. s, 2H), 5.13 (td, J=6.2, 4.0 Hz,     1H), 2.07-1.92 (m, 1H), 1.72-1.57 (t, 1H), 0.73 (t, J=7.4 Hz, 3H).     ES/MS 506.1 (M+H⁺); -   (S)-2-(1-((6-amino-3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)propyl)-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazoline-8-carbonitrile     (Compound 80). ¹H NMR (400 MHz, DMSO-d₆) δ 13.58-12.88 (m, 2H),     8.45-8.34 (m, 2H), 7.99 (d, J=2.4 Hz, 1H), 7.77-7.64 (m, 1H), 7.46     (s, 1H), 6.83 (br. s, 2H), 6.55 (d, J=2.3 Hz, 1H), 5.10-5.17 (m,     1H), 2.13-1.94 (m, 1H), 1.84-1.64 (m, 1H), 0.78 (t, J=7.4 Hz, 3H).     ES/MS 506.1 (M+H⁺); -   (S)-2-(1-((6-amino-3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)propyl)-5,8-dichloro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one     (Compound 81). ¹H NMR (400 MHz, DMSO-d₆) δ 13.29 (br. s, 2H),     8.02-7.89 (m, 2H), 7.57 (d, J=8.5 Hz, 11H), 7.30 (br. s, 1H), 6.81     (br. s, 2H), 6.55 (d, J=2.4 Hz, 1H), 5.05-5.12 (m, 1H), 2.10-1.93     (m, 1H), 1.80-1.60 (m, 1H), 0.77 (t, J=7.4 Hz, 3H). ES/MS 550.1     (M+H⁺); -   (S)-5,8-dichloro-2-(1-((6-chloro-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)propyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one     (Compound 82). ¹H NMR (400 MHz, DMSO-d₆) δ 13.20 (br. s, 1H), 9.03     (d, J=7.0 Hz, 1H), 8.22 (s, 1H), 7.90 (d, J=8.5 Hz, 1H), 7.87 (d,     J=2.4 Hz, 1H), 7.53 (d, J=8.5 Hz, 1H), 6.46 (d, J=2.3 Hz, 1H),     4.60-4.70 (m, 1H), 2.19-2.02 (m, 1H), 1.84 (ddt, J=16.9, 14.4, 7.3     Hz, 1H), 0.85 (t, J=7.3 Hz, 3H). ES/MS 491.99 (M+H⁺); -   (S)-2,4-diamino-6-((1-(3-(4-bromo-1H-pyrazol-3-yl)-5-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile     (Compound 83). ¹H NMR (400 MHz, DMSO-d₆) δ 13.61-13.53 (m, 1H),     8.18-8.03 (m, 1H), 7.87-7.78 (m, 1H), 7.80-7.49 (br. s, 2H),     7.70-7.58 (m, 2H), 7.22 (br. s, 3H), 5.02-4.69 (m, 1H), 2.13-1.90     (m, 1H), 1.84-1.51 (m, 1H), 0.82-0.71 (m, 3H). ES/MS 515.0 (M+H⁺); -   (S)-2,4-diamino-6-((1-(3-(4-bromo-1H-pyrazol-3-yl)-5-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile     (Compound 84). ¹H NMR (400 MHz, DMSO-d₆) δ 13.74-13.41 (m, 1H),     8.21-8.07 (m, 1H), 8.04-7.60 (m, 2H), 7.83 (t, J=8.0 Hz, 1H),     7.78-7.53 (m, 2H), 7.28 (br. s, 2H), 5.21-4.83 (m, 1H), 1.47-1.26     (m, 3H). ES/MS 500.99 (M+H⁺); -   (S)-3-(4-bromo-1H-pyrazol-3-yl)-5,8-dichloro-2-(1-(thiazolo[5,4-d]pyrimidin-7-ylamino)ethyl)quinazolin-4(3H)-one     (Compound 85). ¹H NMR (400 MHz, DMSO-d₆) δ 13.75-13.42 (m, 1H),     9.31-9.20 (m, 1H), 8.53-8.25 (m, 2H), 8.24-8.03 (m, 1H), 8.02-7.90     (m, 1H), 7.66-7.49 (m, 1H), 5.35-4.88 (m, 1H), 1.66-1.35 (m, 3H).     ES/MS 536.9 (M+H⁺); -   (S)-3-(4-bromo-1H-pyrazol-3-yl)-5,8-dichloro-2-(1-(thiazolo[5,4-d]pyrimidin-7-ylamino)propyl)quinazolin-4(3H)-one     (Compound 86). ¹H NMR (400 MHz, DMSO-d₆) δ 13.76-13.34 (m, 1H),     9.31-9.21 (m, 1H), 8.39-8.22 (m, 2H), 8.22-8.03 (m, 1H), 8.02-7.90     (m, 1H), 7.63-7.51 (m, 1H), 5.24-4.77 (m, 1H), 2.28-1.65 (m, 2H),     0.91-0.73 (m, 3H). ES/MS 552.9 (M+H⁺); -   (S)-5-(methylsulfonyl)-3-(1H-pyrazol-3-yl)-2-(1-(thiazolo[5,4-d]pyrimidin-7-ylamino)propyl)quinazolin-4(3H)-one     (Compound 87). ¹H NMR (400 MHz, DMSO-d₆) δ 13.27 (br. s, 1H), 9.28     (s, 1H), 8.46 (d, J=7.2 Hz, 1H), 8.35 (s, 1H), 8.25 (dd, J=7.6, 1.5     Hz, 1H), 8.06-7.81 (m, 3H), 6.50 (d, J=2.3 Hz, 1H), 4.850-4.90 (m,     1H), 3.48 (s, 3H), 2.13-1.73 (m, 2H), 0.80 (t, J=7.2 Hz, 3H). ES/MS     483.1 (M+H⁺); -   (S)-5,8-dichloro-2-(1-((6-chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)propyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one     (Compound 88). ¹H NMR (400 MHz, DMSO-d₆) δ 13.26 (br. s, 1H), 7.96     (d, J=8.5 Hz, 1H), 7.89 (d, J=2.4 Hz, 1H), 7.56 (d, J=8.5 Hz, 1H),     7.37 (d, J=7.7 Hz, 1H), 6.44 (d, J=2.3 Hz, 1H), 5.01-5.09 (m, 1H),     2.62 (s, 3H), 2.12-1.96 (m, 1H), 1.89-1.72 (m, 1H), 0.79 (t, J=7.3     Hz, 3H). ES/MS 504.0 (M+H⁺); -   (S)-5-chloro-2-(1-((6-chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)ethyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one     (Compound 89). ¹H NMR (400 MHz, DMSO-d₆) δ 13.17 (s, 1H), 7.87-7.82     (m, 1H), 7.75 (t, J=8.0 Hz, 1H), 7.70 (d, J=6.7 Hz, 1H), 7.61-7.51     (m, 2H), 6.48 (d, J=2.2 Hz, 1H), 4.96-4.84 (m, 1H), 2.58 (s, 3H),     1.47 (d, J=6.8 Hz, 3H). ES/MS 456.1 (M+H⁺); -   (S)-2-(1-((6-amino-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)ethyl)-5-chloro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one     (Compound 90). ¹H NMR (400 MHz, DMSO-d₆) δ 13.72 (br. s, 1H), 13.16     (s, 1H), 12.64 (s, 1H), 9.66 (s, 1H), 8.41 (s, 1H), 7.84 (d, J=2.4     Hz, 1H), 7.74 (dd, J=8.4, 7.6 Hz, 1H), 7.70-7.25 (m, 2H), 6.62 (d,     J=2.4 Hz, 1H), 4.80-4.92 (m, 1H), 1.50 (d, J=6.8 Hz, 3H). ES/MS     423.1 (M+H⁺); -   (S)-5-chloro-2-(1-((6-chloro-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)ethyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one     (Compound 91). ¹H NMR (400 MHz, DMSO-d₆) δ 13.18 (s, 1H), 9.18 (d,     J=6.5 Hz, 1H), 8.19 (s, 1H), 7.90 (d, J=2.4 Hz, 1H), 7.71 (t, J=8.0     Hz, 1H), 7.59-7.46 (m, 2H), 6.53 (d, J=2.4 Hz, 1H), 4.66-4.78 (m,     1H), 1.49 (d, J=6.8 Hz, 3H). ES/MS 442.0 (M+H⁺); -   (S)-2-(1-((6-amino-3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)ethyl)-5-chloro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one     (Compound 92). ¹H NMR (400 MHz, DMSO-d₆) δ 13.29 (s, 1H), 13.03 (s,     1H), 7.98 (d, J=2.4 Hz, 1H), 7.84-7.71 (m, 2H), 7.70-7.49 (m, 2H),     6.62 (br. s, 2H), 6.55 (d, J=2.3 Hz, 1H), 4.82-4.94 (m, 1H), 1.41     (d, J=6.5 Hz, 3H). ES/MS 501.0 (M+H⁺); -   (S)-2-(1-((2-amino-5-cyano-6-methylpyrimidin-4-yl)amino)propyl)-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazoline-8-carbonitrile     (Compound 93). ¹H NMR (400 MHz, DMSO-d₆) δ 8.44-8.24 (m, 2H),     8.00-7.71 (m, 3H), 7.65 (t, J=7.8 Hz, 1H), 7.40 (s, 2H), 4.84-4.93     (m, 1H), 2.30 (s, 3H), 2.03-1.75 (m, 2H), 0.78 (t, J=7.3 Hz, 3H).     ES/MS 427.1 (M+H⁺); -   (S)-2-(1-((6-chloropyrido[3,2-d]pyrimidin-4-yl)amino)propyl)-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazoline-8-carbonitrile     (Compound 94). ¹H NMR (400 MHz, DMSO-d₆) δ 9.05 (br. d, J=4.7 Hz,     1H), 8.59 (s, 1H), 8.41-8.29 (m, 2H), 8.18 (d, J=8.8 Hz, 1H), 7.96     (d, J=8.7 Hz, 1H), 7.79 (s, 2H), 7.66 (t, J=7.8 Hz, 1H), 5.16-5.25     (m, 1H), 2.19-2.04 (m, 1H), 2.04-1.86 (m, 1H), 0.86 (t, J=7.3 Hz,     3H). ES/MS 458.1 (M+H⁺); -   (S)-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)propyl)-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazoline-8-carbonitrile     (Compound 95). ¹H NMR (400 MHz, DMSO-d₆) δ 8.36 (d, J=7.8 Hz, 2H),     7.87 (br. s, 2H), 7.67 (t, J=7.8 Hz, 1H), 7.62-7.07 (m, 5H),     4.86-4.95 (m, 1H), 2.00-1.83 (m, 1H), 1.84-1.66 (m, 1H), 0.73 (t,     J=7.3 Hz, 3H). ES/MS 437.1 (M+H⁺); -   (S)-2-(1-((2-amino-6-chloro-5-cyanopyrimidin-4-yl)amino)propyl)-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazoline-8-carbonitrile     (Compound 96). ¹H NMR (400 MHz, DMSO-d₆) δ 13.12 (s, 1H), 8.36 (d,     J=7.8 Hz, 2H), 7.81 (d, J=2.4 Hz, 1H), 7.72-7.61 (m, 2H), 7.53 (s,     1H), 7.15 (s, 1H), 6.44 (d, J=2.3 Hz, 1H), 4.86-4.75 (m, 1H),     2.16-1.97 (m, 1H), 1.93-1.75 (m, 1H), 0.81 (t, J=7.2 Hz, 3H). ES/MS     447.1 (M+H⁺); -   (S)-2-(1-((2,6-diamino-5-cyanopyrimidin-4-yl)amino)propyl)-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazoline-5-carbonitrile     (Compound 97). ¹H NMR (400 MHz, DMSO-d₆) δ 13.26 (s, 1H), 8.02 (dd,     J=7.1, 1.6 Hz, 1H), 7.99-7.85 (m, 3H), 6.77 (d, J=7.2 Hz, 1H),     6.66-6.52 (m, 3H), 6.47-5.97 (m, 3H), 4.62-4.47 (m, 1H), 2.02-1.66     (m, 2H), 0.71 (t, J=7.2 Hz, 3H). ES/MS 428.1 (M+H⁺); -   (S)-2,4-diamino-6-((1-(5-bromo-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile     (Compound 98). ¹H NMR (400 MHz, DMSO-d₆) δ 13.20 (s, 1H), 7.91 (s,     1H), 7.76 (dd, J=7.6, 1.4 Hz, 1H), 7.68-7.55 (m, 2H), 6.69 (d, J=7.4     Hz, 1H), 6.57 (d, J=9.7 Hz, 2H), 6.49-6.03 (m, 2H), 4.49-4.58 (m,     1H), 1.99-1.62 (m, 2H), 0.69 (t, J=7.3 Hz, 3H). ES/MS 481.0 (M+H⁺); -   (S)-2,4-diamino-6-((1-(5-bromo-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile     (Compound 99). ¹H NMR (400 MHz, DMSO-d₆) δ 13.18 (s, 1H), 8.13 (s,     1H), 7.77-7.70 (m, 2H), 7.66-7.53 (m, 2H), 6.64 (d, J=7.5 Hz, 1H),     6.57 (s, 2H), 6.33 (s, 2H), 4.63-4.73 (m, 1H), 1.86-1.57 (m, 2H),     0.67 (t, J=7.2 Hz, 3H). ES/MS 481.0 (M+H⁺); -   (S)-5-bromo-3-(1H-pyrazol-4-yl)-2-(1-(thiazolo[5,4-d]pyrimidin-7-ylamino)propyl)quinazolin-4(3H)-one     (Compound 100). ¹H NMR (400 MHz, DMSO-d₆) δ 13.19 (s, 1H), 9.28 (s,     1H), 8.43 (d, J=6.8 Hz, 1H), 8.39 (s, 1H), 8.08 (s, 1H), 7.76-7.63     (m, 2H), 7.63-7.51 (m, 2H), 4.86-4.95 (m, 1H), 2.07-1.84 (m, 4H),     0.79 (t, J=7.3 Hz, 3H). ES/MS 482.7 (M+H⁺); -   (S)-5-bromo-3-(1H-pyrazol-3-yl)-2-(1-(thiazolo[5,4-d]pyrimidin-7-ylamino)propyl)quinazolin-4(3H)-one     (Compound 101). ¹H NMR (400 MHz, DMSO-d₆) δ 13.20 (s, 1H), 9.28 (s,     1H), 8.37-8.27 (m, 2H), 7.88 (t, J=2.0 Hz, 1H), 7.75 (dd, J=7.0, 2.1     Hz, 1H), 7.67-7.55 (m, 2H), 6.47 (t, J=2.2 Hz, 1H), 4.88-4.75 (m,     1H), 2.09-1.77 (m, 2H), 0.78 (t, J=7.3 Hz, 3H). ES/MS 483.00 (M+H⁺); -   (S)-2-(1-((2,6-diamino-5-cyanopyrimidin-4-yl)amino)propyl)-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazoline-5-carbonitrile     (Compound 102). ¹H NMR (400 MHz, DMSO-d₆) δ 8.03 (dd, J=7.2, 1.5 Hz,     1H), 8.00-7.87 (m, 4H), 7.78-6.83 (m, 5H), 4.73-4.81 (m, 1H),     1.71-1.91 (m, 2H), 0.70 (t, J=7.3 Hz, 3H). ES/MS 427.9 (M+H⁺); -   (S)-4-oxo-3-(1H-pyrazol-4-yl)-2-(1-(thiazolo[5,4-d]pyrimidin-7-ylamino)propyl)-3,4-dihydroquinazoline-5-carbonitrile     (Compound 103). ¹H NMR (400 MHz, DMSO-d₆) δ 9.29 (s, 1H), 8.50 (d,     J=7.1 Hz, 1H), 8.40 (s, 1H), 8.00 (dd, J=6.6, 2.1 Hz, 1H), 7.96-7.81     (m, 4H), 4.90-5.00 (m, 1H), 2.01-1.86 (m, 2H), 0.80 (t, J=7.3 Hz,     3H). ES/MS 429.8 (M+H⁺); -   (S)-3-(4-bromo-1H-pyrazol-3-yl)-5-chloro-2-(1-(thiazolo[5,4-d]pyrimidin-7-ylamino)ethyl)quinazolin-4(3H)-one     (Compound 104). ¹H NMR (400 MHz, DMSO-d₆) δ 13.61 (br. s, 1H),     9.30-9.23 (m, 1H), 8.55 (d, J=7.0 Hz, 1H), 8.36-8.27 (m, 1H),     8.23-8.08 (m, 1H), 7.83-7.69 (m, 1H), 7.69-7.53 (m, 2H), 5.34-4.80     (m, 1H), 1.62-1.35 (m, 3H). ES/MS 502.9 (M+H⁺); -   (S)-2,4-diamino-6-(((5-chloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)(phenyl)methyl)amino)pyrimidine-5-carbonitrile     (compound 105). ¹H NMR (400 MHz, DMSO-d₆) δ 7.95-7.56 (m, 4H), 7.44     (s, 2H), 7.46-6.88 (m, 6H), 6.29-5.90 (m, 1H). ES/MS 484.8 (M+H⁺); -   (S)-2,4-diamino-6-(((5-chloro-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazolin-2-yl)(phenyl)methyl)amino)pyrimidine-5-carbonitrile     (compound 106). ¹H NMR (400 MHz, DMSO-d₆) δ 7.85 (t, J=8.0 Hz, 2H),     7.65 (ddd, J=10.4, 8.1, 1.2 Hz, 2H), 7.36-7.00 (m, 6H), 6.02 (d,     J=6.8 HZ, 1H). ES/MS 484.8 (M+H⁺); -   (S)-5-chloro-2-(((2,6-diamino-5-chloropyrimidin-4-yl)amino)(phenyl)methyl)-3-(1H-pyrazol-4-yl)quinazolin-4(3h)-one     (compound 107). ¹H NMR (400 MHz, DMSO-d₆) δ 7.84 (t, J=8.0 Hz, 2H),     7.75 (dd, J=8.1, 1.2 Hz, 1H), 7.65 (dd, J=7.8, 1.2 Hz, 2H),     7.33-7.16 (m, 3H), 7.18-7.02 (m, 2H), 6.01 (d, J=6.9 HZ, 1H). ES/MS     494.1 (M+H⁺); -   (S)-2-amino-4-(((5-chloro-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazolin-2-yl)(phenyl)methyl)amino)-6-methylpyrimidine-5-carbonitrile     (compound 108). ¹H NMR (400 MHz, DMSO-d₆) δ 7.84 (t, J=8.0 Hz, 2H),     7.65 (ddd, J=9.8, 8.0, 1.2 Hz, 2H), 7.39-7.16 (m, 4H), 7.20-7.05 (m,     2H), 6.01 (d, J=6.7 HZ, 1H), 2.36-2.17 (M, 3H). ES/MS 484.1 (M+H⁺); -   (S)-5-chloro-2-(((2,6-diamino-5-chloropyrimidin-4-yl)amino)(phenyl)methyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3h)-one     (compound 109). ¹H NMR (400 MHz, DMSO-d₆) δ 13.16 (s, 1H), 7.99-7.51     (m, 4H), 7.23 (t, J=3.5 Hz, 3H), 7.15-6.75 (m, 2H), 6.16 (d, J=7.2     Hz, 1H), 6.00 (S, 1H). ES/MS 494.1 (M+H⁺); -   (S)-2-amino-4-(((5-chloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)(phenyl)methyl)amino)-6-methylpyrimidine-5-carbonitrile     (compound 110). ¹H NMR (400 MHz, DMSO-d₆) δ 7.92-7.75 (m, 2H), 7.66     (ddd, J=7.9, 5.4, 1.2 Hz, 2H), 7.39-7.04 (m, 6H), 6.22-6.00 (m, 1H),     2.28 (d, J=2.1 HZ, 3H). ES/MS 484.1 (M+H⁺); -   (S)-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-6-fluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3h)-one     (compound 111). ¹H NMR (400 MHz, DMSO-d₆) δ 13.21 (s, 1H), 7.92 (dd,     J=2.4, 1.7 Hz, 1H), 7.85-7.63 (m, 2H), 6.57 (t, J=2.2 Hz, 1H), 6.25     (d, J=7.4 HZ, 1H), 5.96 (s, 2H), 5.50 (s, 2H), 4.62 (p, J=6.8 Hz,     1H), 1.34 (d, J=6.7 Hz, 3H). ES/MS 416.1 (M+H⁺); -   (S)-2,4-diamino-6-((1-(6-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile     (compound 112). ¹H NMR (400 MHz, DMSO-d₆) δ 13.20 (s, 1H), 8.11-7.85     (m, 1H), 7.85-7.63 (m, 3H), 6.68 (d, J=7.4 Hz, 1H), 6.65-6.34 (m,     3H), 6.36-6.03 (m, 2H), 4.59 (td, J=7.9, 3.9 HZ, 1H), 2.07-1.83 (m,     1H), 1.71 (dt, J=14.4, 7.5 Hz, 1H), 0.69 (t, J=7.2 Hz, 3H). ES/MS     421.2 (M+H⁺); -   (S)-2,4-diamino-6-((cyclopropyl(6-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)methyl)amino)pyrimidine-5-carbonitrile     (compound 113). ¹H NMR (400 MHz, DMSO-d₆) δ 13.34-13.06 (m, 1H),     7.98-7.63 (m, 4H), 6.60 (s, 2H), 6.48-6.36 (m, 2H), 6.28 (s, 2H),     4.75 (t, J=7.1 HZ, 2H), 1.26 (d, J=7.5 Hz, 1H), 0.41-0.21 (m, 3H),     0.23-0.08 (m, 1H). ES/MS 433.2 (M+H⁺) -   (S)-2-(cyclopropyl((2,6-diamino-5-chloropyrimidin-4-yl)amino)methyl)-6-fluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3h)-one     (compound 114). ¹H NMR (400 MHz, DMSO-d₆) δ 13.23 (s, 1H), 7.92 (dd,     J=2.4, 1.6 Hz, 1H), 7.85-7.61 (m, 3H), 6.47 (t, J=2.2 Hz, 1H), 5.99     (d, J=7.5 Hz, 3H), 5.52 (s, 2H), 4.72 (dd, J=8.0, 6.5 Hz, 1H), 1.18     (dd, J=13.3, 6.5 Hz, 1H), 0.39-0.09 (m, 4H). ES/MS 442.1 (M+H⁺); -   (S)-2,4-diamino-6-((1-(6-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile     (compound 115). ¹H NMR (400 MHz, DMSO-d₆) δ 13.18 (d, J=2.2 Hz, 1H),     7.90 (dd, J=2.4, 1.4 Hz, 1H), 7.87-7.58 (m, 2H), 6.80 (d, J=6.8 Hz,     1H), 6.67-6.40 (m, 2H), 6.26 (s, 2H), 4.81-4.59 (m, 1H), 1.36 (d,     J=6.8 Hz, 3H). ES/MS 407.1 (M+H⁺); -   (S)-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)propyl)-6-fluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3h)-one     (compound 116). ¹H NMR (400 MHz, DMSO-d₆) δ 13.22 (s, 1H), 7.93 (dd,     J=2.4, 1.6 Hz, 1H), 7.85-7.56 (m, 3H), 6.59 (t, J=2.2 Hz, 1H),     6.23-5.90 (m, 3H), 5.51 (s, 2H), 4.53 (td, J=8.2, 3.7 Hz, 1H), 1.90     (ddd, J=13.8, 7.2, 3.7 Hz, 1H), 1.67 (dt, J=14.5, 7.4 Hz, 1H), 0.70     (T, J=7.3 HZ, 3H). ES/MS 430.1 (M+H⁺); -   (S)-8-chloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-6-fluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3h)-one     (compound 123). ¹H NMR (400 MHz, DMSO-d₆) δ 13.26 (s, 1H), 8.10 (dd,     J=8.5, 2.9 Hz, 1H), 7.94 (dd, J=2.4, 1.6 Hz, 1H), 7.78 (dd, J=8.2,     2.9 Hz, 1H), 6.53 (t, J=2.2 Hz, 1H), 6.39 (d, J=7.5 Hz, 1H), 5.97     (s, 2H), 5.55 (s, 2H), 4.71 (dd, J=7.4, 6.6 Hz, 1H), 1.33 (d, J=6.6     Hz, 3H). ES/MS 450.1 (M+H⁺); -   (S)-5-chloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)butyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3h)-one     (compound 124). ¹H NMR (400 MHz, DMSO-d₆) δ 13.23 (d, J=4.4 Hz, 1H),     7.96 (d, J=2.2 Hz, 1H), 7.75 (t, J=8.0 Hz, 1H), 7.56 (tt, J=5.7, 1.4     Hz, 2H), 6.66 (t, J=2.2 Hz, 1H), 6.18-5.93 (m, 2H), 5.50 (s, 2H),     4.60 (t, J=8.9 Hz, 1H), 1.82 (t, J=9.9 Hz, 1H), 1.70 (d, J=11.4 Hz,     1H), 1.30 (d, J=11.8 Hz, 1H), 1.10 (dt, J=14.3, 7.5 Hz, 1H), 0.65     (t, J=7.3 HZ, 3H). ES/MS 460.1 (M+H⁺); -   (S)-2,4-diamino-6-(((8-chloro-6-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)(cyclopropyl)methyl)amino)pyrimidine-5-carbonitrile     (compound 125). ¹H NMR (400 MHz, DMSO-d₆) δ 13.38-13.15 (m, 1H),     8.14 (dd, J=8.5, 2.9 Hz, 1H), 7.94 (dd, J=2.4, 1.6 Hz, 1H), 7.82     (dd, J=8.1, 2.9 Hz, 1H), 6.65 (s, 2H), 6.52-6.42 (m, 2H), 6.36 (s,     2H), 4.96 (dd, J=7.7, 6.2 Hz, 1H), 1.43-1.26 (m, 1H), 0.50-0.29 (m,     3H), 0.18 (tt, J=8.5, 3.3 Hz, 1H). ES/MS 467.1 (M+H⁺); and -   (S)-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-5-(difluoromethyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one     (Compound 126). ¹H NMR (400 MHz, DMSO-d₆) δ 13.23 (s, 1H), 8.01-7.68     (m, 5H), 6.59 (t, J=2.2 Hz, 1H), 6.33 (br. s, 1H), 6.03 (br. s, 2H),     5.59 (br. s, 2H), 4.67-4.55 (m, 1H), 1.36 (d, J=6.7 Hz, 3H). ES/MS     448.1 (M+H⁺). -   (S)-5-chloro-2-(cyclobutyl((2,6-diamino-5-chloropyrimidin-4-yl)amino)methyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one     (Compound 127). ¹H NMR (400 MHz, DMSO-d₆) δ 7.94-7.89 (m, 1H), 7.75     (t, J=8.0 Hz, 1H), 7.61 (dd, J=8.2, 1.1 Hz, 1H), 7.55 (dd, J=7.8,     1.3 Hz, 1H), 6.46 (t, J=2.2 Hz, 1H), 6.07-5.95 (m, 3H), 5.50 (s,     2H), 4.89 (dd, J=8.7, 5.9 Hz, 1H), 1.90-1.55 (m, 8H). ES/MS 572.1     (M+H⁺). -   (S)-2,4-diamino-6-(((5-chloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)(cyclobutyl)methyl)amino)pyrimidine-5-carbonitrile     (Compound 128). ¹H NMR (400 MHz, DMSO-d₆) δ 7.86 (dd, J=2.4, 1.6 Hz,     1H), 7.80-7.75 (m, 1H), 7.61 (d, J=1.2 Hz, 1H), 7.58 (dd, J=4.0, 1.2     Hz, 1H), 7.56 (d, J=1.2 Hz, 0H), 6.62 (s, 2H), 6.47 (s, 1H),     6.43-6.37 (m, 2H), 5.01 (dd, J=8.2, 6.3 Hz, 1H), 2.07 (s, 1H),     1.90-1.57 (m, 8H). ES/MS 463.1 (M+H⁺). -   (S)-8-chloro-2-(cyclobutyl((2,6-diamino-5-chloropyrimidin-4-yl)amino)methyl)-6-fluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one     (Compound 129). ¹H NMR (400 MHz, DMSO-d₆) δ 8.12 (dd, J=8.5, 2.9 Hz,     1H), 7.93 (dd, J=2.4, 1.6 Hz, 1H), 7.80 (dd, J=8.2, 2.9 Hz, 1H),     6.47 (t, J=2.2 Hz, 1H), 6.21 (d, J=8.7 Hz, 1H), 6.04 (s, 2H), 5.53     (s, 2H), 4.99 (dd, J=8.7, 5.2 Hz, 1H), 1.83-1.58 (m, 6H), 1.38-1.21     (m, 2H). ES/MS 490.1 (M+H⁺). -   (S)-2,4-diamino-6-(((8-chloro-6-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)(cyclobutyl)methyl)amino)pyrimidine-5-carbonitrile     (Compound 130). ¹H NMR (400 MHz, DMSO-d₆) δ 8.13 (dt, J=8.6, 3.0 Hz,     2H), 7.88-7.77 (m, 1H), 6.69-6.36 (m, 1H), 5.15 (dd, J=8.3, 5.8 Hz,     4H), 3.01-2.90 (m, 1H), 2.02-1.58 (m, 7H). ES/MS 481.1 (M+H⁺). -   (S)-2,4-diamino-6-((cyclobutyl(5-(difluoromethyl)-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)methyl)amino)pyrimidine-5-carbonitrile     (Compound 131). ¹H NMR (400 MHz, DMSO-d₆) δ 8.00 (t, J=7.9 Hz, 1H),     7.90-7.85 (m, 3H), 6.63 (s, 2H), 6.46-6.39 (m, 2H), 5.08 (s, J=8.2,     6.5 Hz, 4H), 1.95-1.58 (m, 2H), 1.28-1.14 (m, 7H). ES/MS 479.2     (M+H⁺). -   (S)-2-(cyclobutyl((2,6-diamino-5-chloropyrimidin-4-yl)amino)methyl)-5-(difluoromethyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one     (Compound 132). ¹H NMR (400 MHz, DMSO-d₆) δ 8.06-7.92 (m, 3H), 7.87     (dt, J=7.4, 3.3 Hz, 3H), 6.50 (dt, J=4.4, 2.2 Hz, 1H), 6.09-5.97 (m,     2H), 5.51 (s, 2H), 4.95 (dd, J=8.7, 6.0 Hz, 1H), 4.03 (q, J=7.1 Hz,     1H), 1.90-1.60 (m, 6H). ES/MS 488.1 (M+H⁺). -   (S)-2,4-diamino-6-((cyclopropyl(4-oxo-3-(1H-pyrazol-3-yl)-8-(trifluoromethyl)-3,4-dihydroquinazolin-2-yl)methyl)amino)pyrimidine-5-carbonitrile     (Compound 133). ¹H NMR (400 MHz, DMSO-d₆) δ 8.05-7.97 (m, 1H), 7.91     (dd, J=2.4, 1.7 Hz, 2H), 6.64 (s, 1H), 6.51-6.44 (m, 2H), 4.76 (t,     J=7.3 Hz, 1H), 0.38 (dd, J=16.1, 6.7 Hz, 6H). ES/MS 483.1 (M+H⁺). -   (S)-2-(cyclopropyl((2,6-diamino-5-chloropyrimidin-4-yl)amino)methyl)-3-(1H-pyrazol-3-yl)-8-(trifluoromethyl)quinazolin-4(3H)-one     (Compound 134). ¹H NMR (400 MHz, DMSO-d₆) δ 8.04-7.96 (m, 1H), 6.52     (t, J=2.2 Hz, 2H), 6.03 (d, J=9.7 Hz, 1H), 5.56 (d, 1H), 4.72 (dd,     J=7.9, 6.7 Hz, 1H), 1.25 (s, 1H), 0.41-0.29 (m, 5H) ES/MS 492.1     (M+H⁺). -   (S)-2,4-diamino-6-((1-(4-oxo-3-(1H-pyrazol-3-yl)-8-(trifluoromethyl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile     (Compound 135). ¹H NMR (400 MHz, DMSO-d₆) δ 8.03-7.92 (m, 1H), 6.87     (d, J=6.8 Hz, 1H), 6.64-6.56 (m, 2H), 6.31 (s, 1H), 4.72 (t, J=6.8     Hz, 1H), 1.43 (m, 1H), 1.41 (d, J=6.7 Hz, 3H). ES/MS 457.1 (M+H⁺). -   (S)-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-3-(1H-pyrazol-3-yl)-8-(trifluoromethyl)quinazolin-4(3H)-one     (Compound 136). ¹H NMR (400 MHz, DMSO-d₆) δ 8.06-7.93 (m, 3H), 6.64     (t, J=2.2 Hz, 1H), 6.02 (s, 1H), 5.57 (s, 1H), 4.64 (t, J=7.0 Hz,     1H), 1.42 (m, 1H), 1.39 (d, J=6.7 Hz, 3H). ES/MS 466.1 (M+H⁺). -   (S)-2,4-diamino-6-((1-(8-(difluoromethyl)-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile     (Compound 137). ¹H NMR (400 MHz, DMSO) δ 13.23 (br s, 1H), 8.33-8.28     (m, 1H), 8.18-8.13 (m, 1H), 7.92 (d, J=2.4 Hz, 1H), 7.88-7.57 (m,     5H), 6.53 (d, J=2.4 Hz, 1H), 4.95 (p, J=6.7 Hz, 1H), 1.43 (d, J=6.7     Hz, 3H). ES/MS 439.1 (M+H⁺); -   (S)-2,4-diamino-6-((1-(6-chloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile     (Compound 137). ¹H NMR (400 MHz, DMSO) δ 13.21 (br s, 1H), 8.08 (dd,     J=2.5, 0.5 Hz, 1H), 7.94-7.88 (m, 2H), 7.73 (dd, J=8.7, 0.5 Hz, 1H),     6.53 (d, J=2.3 Hz, 1H), 4.91-4.82 (m, 1H), 1.42 (d, J=6.7 Hz, 3H).     ES/MS 423.1 (M+H⁺); -   (S)-2,4-diamino-6-((1-(7-chloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile     (Compound 138). ¹H NMR (400 MHz, DMSO) δ 13.21 (br s, 1H), 8.14 (dd,     J=8.5, 0.4 Hz, 1H), 7.90 (d, J=2.4 Hz, 1H), 7.72 (dd, J=2.1, 0.4 Hz,     11H), 7.62 (dd, J=8.5, 2.1 Hz, 1H), 6.54 (d, J=2.3 Hz, 1H), 4.83 (p,     J=6.7 Hz, 1H), 1.42 (d, J=6.8 Hz, 3H). ES/MS 423.1 (M+H⁺); -   (S)-2,4-diamino-6-((cyclopropyl(8-(difluoromethyl)-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)methyl)amino)pyrimidine-5-carbonitrile     (Compound 140). ¹H NMR (400 MHz, DMSO) δ 13.25 (br s, 1H), 8.10-8.00     (m, 2H), 7.93 (d, J=2.4 Hz, 1H), 7.88-7.50 (m, 3H), 6.53 (d, J=2.3     Hz, 1H), 4.95 (p, J=6.7 Hz, 1H), 1.42 (d, J=6.7 Hz, 3H). ES/MS 457.1     (M+H⁺); -   (S)-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-8-(difluoromethyl)-6-fluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one     (Compound 141). ¹H NMR (400 MHz, DMSO) δ 13.26 (bs, 1H), 8.10-8.01     (m, 2H), 7.92 (d, J=2.4 Hz, 1H), 7.83-7.20 (m, 6H), 6.52 (d, J=2.3     Hz, 1H), 4.93 (p, J=6.7 Hz, 1H), 1.43 (d, J=6.7 Hz, 3H). ES/MS 466.1     (M+H⁺); -   (S)-2-amino-4-(difluoromethyl)-6-((1-(8-(difluoromethyl)-6-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile     (Compound 142). ¹H NMR (400 MHz, DMSO) δ 13.22 (s, 1H), 8.07 (dd,     J=8.6, 3.0 Hz, 1H), 8.02 (dd, J=8.2, 3.0 Hz, 1H), 7.89 (d, J=2.4 Hz,     1H), 7.86-7.51 (m, 3H), 7.26 (br s, 1H), 6.84-6.51 (m, 2H), 4.96 (p,     J=6.7 Hz, 1H), 1.45 (d, J=6.7 Hz, 3H). ES/MS 492.1 (M+H⁺); -   (S)-2,4-diamino-6-((cyclopropyl(8-(difluoromethyl)-6-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)methyl)amino)pyrimidine-5-carbonitrile     (Compound 143). ¹H NMR (400 MHz, DMSO) δ 13.19 (br s, 1H), 8.09 (dd,     J=8.6, 3.0 Hz, 1H), 8.03 (dd, J=8.1, 3.0 Hz, 1H), 7.90-7.59 (m, 2H),     6.41 (d, J=2.4 Hz, 1H), 4.87 (t, J=7.5 Hz, 1H), 1.50-1.39 (m, 1H),     0.50-0.37 (m, 3H), 0.21-0.14 (m, 2H). ES/MS 482.1 (M+H⁺); -   (S)-2-(cyclopropyl((2,6-diamino-5-chloropyrimidin-4-yl)amino)methyl)-8-(difluoromethyl)-6-fluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one     (Compound 144). ¹H NMR (400 MHz, DMSO) δ 13.19 (br s, 1H), 8.09 (dd,     J=8.7, 3.0 Hz, 1H), 8.03 (dd, J=8.2, 3.0 Hz, 1H), 7.89-7.58 (m, 2H),     7.52-7.15 (m, 3H), 6.39 (d, J=2.3 Hz, 1H), 4.84 (t, J=7.7 Hz, 1H),     1.49-1.39 (m, 1H), 0.53-0.39 (m, 3H), 0.21-0.13 (m, 1H). ES/MS 492.1     (M+H⁺); -   (S)-2-amino-4-((cyclopropyl(8-(difluoromethyl)-6-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)methyl)amino)-6-(difluoromethyl)pyrimidine-5-carbonitrile     (Compound 145). ¹H NMR (400 MHz, DMSO) δ 13.15 (br s, 1H), 8.08 (dd,     J=8.7, 3.0 Hz, 1H), 8.03 (dd, J=8.3, 3.0 Hz, 1H), 7.90-7.54 (m, 3H),     7.43 (d, J=7.6 Hz, 1H), 7.26 (br s, 1H), 6.83-6.50 (t, J=53.4 Hz,     1H), 6.39 (d, J=2.4 Hz, 1H), 4.92 (t, J=7.5 Hz, 1H), 1.51-1.43 (m,     1H), 0.53-0.39 (m, 3H), 0.21-0.13 (m, 1H). ES/MS 518.1 (M+H⁺); -   (S)-5-chloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)-2-methylpropyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one     (Compound 146). ¹H NMR (400 MHz, DMSO) δ 13.24 (br s, 1H), 7.93 (d,     J=2.4 Hz, 1H), 7.83-7.78 (m, 1H), 7.67 (dd, J=8.2, 1.2 Hz, 1H), 7.62     (dd, J=7.8, 1.2 Hz, 1H), 7.50 (br s, 2H), 7.27 (br s, 2H), 7.05 (br     s, 1H), 6.46 (d, J=2.3 Hz, 1H), 4.96-4.89 (m, 1H), 2.26-2.16 (m,     1H), 0.82 (d, J=2.7 Hz, 3H), 0.81 (d, J=2.8 Hz, 3H). ES/MS 460.1     (M+H⁺); -   (S)-8-chloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-5-fluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one     (Compound 147). ¹H NMR (400 MHz, DMSO) δ 13.26 (br s, 1H), 8.07 (dd,     J=8.9, 4.8 Hz, 1H), 7.93 (d, J=2.4 Hz, 1H), 7.68 (d, J=6.8 Hz, 1H),     7.45 (br s, 2H), 7.40 (dd, J=10.5, 8.9 Hz, 1H), 6.49 (d, J=2.3 Hz,     1H), 4.88 (p, J=6.7 Hz, 1H), 1.43 (d, J=6.7 Hz, 3H). ES/MS 450.1     (M+H⁺); -   (S)-8-chloro-2-(cyclopropyl((2,6-diamino-5-chloropyrimidin-4-yl)amino)methyl)-5-fluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one     (Compound 148). ¹H NMR (400 MHz, DMSO) δ 13.24 (br s, 1H), 8.08 (dd,     J=8.9, 4.8 Hz, 1H), 7.90 (d, J=2.4 Hz, 1H), 7.51-7.24 (m, 4H), 6.40     (d, J=2.3 Hz, 1H), 4.94-4.87 (m, 1H), 1.43-1.35 (m, 1H), 0.51-0.36     (m, 3H), 0.22-0.13 (m, 1H). ES/MS 476.1 (M+H⁺); -   (R)-8-chloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)-2-hydroxyethyl)-6-fluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one     (Compound 149). ¹H NMR (400 MHz, DMSO) δ 13.30 (br s, 1H), 8.15 (dd,     J=8.5, 2.9 Hz, 1H), 7.97 (d, J=2.4 Hz, 1H), 7.85 (dd, J=8.1, 2.9 Hz,     1H), 7.39 (br s, 3H), 6.53 (d, J=2.3 Hz, 1H), 4.95-4.89 (m, 1H),     3.78-3.70 (m, 2H). ES/MS 466.1 (M+H⁺); -   (S)-2-(1-((5-bromothieno[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-chloro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one     (Compound 150). ¹H NMR (400 MHz, DMSO) δ 13.36 (br s, 1H), 8.40 (s,     1H), 8.38 (d, J=6.8 Hz, 1H), 8.03 (d, J=2.4 Hz, 1H), 7.89 (s, 1H),     7.86-7.79 (m, 2H), 7.63 (dd, J=6.5, 2.5 Hz, 1H), 6.57 (d, J=2.3 Hz,     1H), 5.12 (p, J=6.6 Hz, 1H), 1.44 (d, J=6.5 Hz, 3H). ES/MS 502.0     (M+H⁺); -   (S)-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-5-fluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one     (Compound 151). ¹H NMR (400 MHz, DMSO) δ 13.21 (br s, 1H), 7.90 (d,     J=2.3 Hz, 1H), 7.89-7.82 (m, 1H), 7.71 (d, J=6.7 Hz, 1H), 7.56-7.48     (m, 2H), 7.43-7.28 (m, 4H), 6.53 (d, J=2.4 Hz, 1H), 4.79 (p, J=6.7     Hz, 1H), 1.43 (d, J=6.8 Hz, 3H). ES/MS 416.1 (M+H⁺); -   (S)-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-5,8-difluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one     (Compound 152). ¹H NMR (400 MHz, DMSO) δ 13.24 (br s, 1H), 7.91 (d,     J=2.4 Hz, 1H), 7.81 (td, J=9.5, 4.1 Hz, 1H), 7.67 (br s, 1H), 7.44     (br s, 2H), 7.37 (ddd, J=10.3, 9.0, 3.6 Hz, 1H), 7.30 (br s, 2H),     6.53 (d, J=2.3 Hz, 1H), 4.80 (p, J=6.7 Hz, 1H), 1.44 (d, J=6.7 Hz,     3H). ES/MS 434.1 (M+H⁺); -   (S)-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-8-fluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one     (Compound 153). ¹H NMR (400 MHz, DMSO) δ 13.24 (br s, 1H), 7.98-7.94     (m, 1H), 7.91 (d, J=2.4 Hz, 1H), 7.78 (ddd, J=10.5, 8.1, 1.4 Hz,     1H), 7.72 (d, J=6.7 Hz, 1H), 7.58 (td, J=8.1, 4.7 Hz, 1H), 7.48 (br     s, 2H), 7.33 (br s, 2H), 6.54 (d, J=2.3 Hz, 1H), 4.85 (p, J=6.6 Hz,     1H), 1.45 (d, J=6.7 Hz, 3H). ES/MS 416.1 (M+H⁺); -   (S)-5-chloro-3-(5-chloro-1H-pyrazol-3-yl)-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)quinazolin-4(3H)-one     (Compound 154). ¹H NMR (400 MHz, DMSO) δ 7.86-7.80 (m, 1H), 7.75 (br     s, 1H), 7.67-7.62 (m, 2H), 7.51 (br s, 2H), 7.40 (br s, 2H), 6.61     (s, 1H), 4.98-4.80 (m, 1H), 1.45 (d, J=6.7 Hz, 3H). ES/MS 466.0     (M+H⁺); -   (S)-5-chloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-3-(5-fluoro-1H-pyrazol-3-yl)quinazolin-4(3H)-one     (Compound 155). ¹H NMR (400 MHz, DMSO) δ 13.01 (br s, 1H), 7.89-7.25     (m, 8H), 6.37 (br s, 1H), 4.90-4.75 (s, 1H), 1.48-1.44 (m, 3H).     ES/MS 450.1 (M+H⁺); -   (S)-8-chloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one     (Compound 156). ¹H NMR (400 MHz, DMSO) δ 13.26 (br s, 1H), 8.11 (dd,     J=7.9, 1.4 Hz, 1H), 8.07 (dd, J=7.9, 1.4 Hz, 1H), 7.93 (d, J=2.4 Hz,     1H), 7.75 (br s, 1H), 7.58 (t, J=7.9 Hz, 1H), 7.47 (br s, 1H), 7.38     (br s, 1H), 6.50 (d, J=2.3 Hz, 1H), 4.92 (p, J=6.6 Hz, 1H), 1.44 (d,     J=6.6 Hz, 3H). ES/MS 432.1 (M+H⁺); -   (S)-5-chloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-3-(1H-pyrazol-4-yl)quinazolin-4(3H)-one     (Compound 157). ¹H NMR (400 MHz, DMSO) δ 7.88 (s, 2H), 7.81-7.70 (m,     2H), 7.66-7.54 (m, 4H), 7.48 (br s, 2H), 4.90 (p, J=6.7 Hz, 1H),     1.39 (d, J=6.7 Hz, 3H). ES/MS 432.1 (M+H⁺); -   (S)-5,8-dichloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-3-(1H-pyrazol-4-yl)quinazolin-4(3H)-one     (Compound 158). ¹H NMR (400 MHz, DMSO) δ 8.00 (d, J=8.5 Hz, 1H),     7.86 (br s, 2H), 7.74 (br s, 1H), 7.60 (d, J=8.6 Hz, 1H), 7.50 (br     s, 3H), 4.95 (p, J=6.7 Hz, 1H), 1.39 (d, J=6.6 Hz, 3H). ES/MS 466.0     (M+H⁺); -   (S)-5-chloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-8-fluoro-3-(1H-pyrazol-4-yl)quinazolin-4(3H)-one     (Compound 159). ¹H NMR (400 MHz, DMSO) δ 7.86 (br s, 4H), 7.78-7.71     (m, 1H), 7.60 (dd, J=8.8, 4.5 Hz, 1H), 7.46 (br s, 3H), 4.90 (p,     J=6.8 Hz, 1H), 1.39 (d, J=6.7 Hz, 3H). ES/MS 450.1 (M+H⁺); -   (R)-5-chloro-2-(cyclopropyl((2,6-diamino-5-chloropyrimidin-4-yl)amino)methyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one     (Compound 160). ¹H NMR (400 MHz, DMSO) δ 13.13 (br s, 1H), 7.82 (d,     J=2.4 Hz, 1H), 7.79 (t, J=8.0 Hz, 1H), 7.67 (dd, J=8.2, 1.2 Hz, 1H),     7.60 (dd, J=7.8, 1.2 Hz, 1H), 7.52-7.42 (m, 3H), 7.34 (br s, 2H),     6.34 (d, J=2.3 Hz, 1H), 4.68 (t, J=7.7 Hz, 1H), 1.39-1.28 (m, 1H),     0.50-0.34 (m, 3H), 0.18-0.10 (m, 1H). ES/MS 458.1 (M+H⁺); -   (S)-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-6,8-difluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one     (Compound 161). ¹H NMR (400 MHz, DMSO) δ 13.22 (br s, 1H), 7.95-7.85     (m, 1H), 7.87 (d, J=2.3 Hz, 1H), 7.74-7.69 (m, 1H), 7.67 (ddd,     J=8.3, 3.0, 1.3 Hz, 1H), 7.50 (br s, 2H), 7.36 (br s, 2H), 6.49 (d,     J=2.4 Hz, 1H), 4.83 (p, J=6.7 Hz, 1H), 1.41 (d, J=6.7 Hz, 3H). ES/MS     434.1 (M+H⁺); -   (S)-2-(cyclopropyl((2,6-diamino-5-chloropyrimidin-4-yl)amino)methyl)-6,8-difluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one     (Compound 162). ¹H NMR (400 MHz, DMSO) δ 13.16 (br s, 1H), 7.92     (ddd, J=10.3, 9.0, 2.9 Hz, 1H), 7.82 (d, J=2.4 Hz, 1H), 7.68 (ddd,     J=8.3, 2.8, 1.3 Hz, 1H), 7.49 (br s, 3H), 7.33 (br s, 2H), 6.32 (d,     J=2.3 Hz, 1H), 4.72 (t, J=7.8 Hz, 1H), 1.42-1.33 (m, 1H), 0.52-0.35     (m, 3H), 0.19-0.11 (m, 1H). ES/MS 460.1 (M+H⁺); -   (S)-5-chloro-2-(1-((2,6-diaminopyrimidin-4-yl)amino)ethyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one     (Compound 163). ¹H NMR (400 MHz, DMSO) δ 13.17 (s, 1H), 10.89 (s,     1H), 8.22 (d, J=6.6 Hz, 1H), 7.89 (s, 1H), 7.78-7.70 (m, 1H),     7.60-7.52 (m, 2H), 7.11 (s, 1H), 7.02 (s, 1H), 6.66 (d, J=2.4 Hz,     1H), 5.17 (s, 1H), 4.57-4.47 (m, 1H), 1.34 (d, J=6.9 Hz, 3H). ES/MS     398.1 (M+H⁺); -   (S)-2-(1-((6-amino-5-chloropyrimidin-4-yl)amino)ethyl)-5-chloro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one     (Compound 164). ¹H NMR (400 MHz, DMSO) δ 13.19 (s, 1H), 7.92 (s,     1H), 7.88 (d, J=2.4 Hz, 1H), 7.75 (dd, J=7.8 Hz, 1H), 7.60 (dd,     J=8.2, 1.2 Hz, 1H), 7.56 (dd, J=7.8, 1.2 Hz, 1H), 7.20 (br s, 1H),     7.03 br (s, 2H), 6.44 (d, J=2.4 Hz, 1H), 4.77 (p, J=6.7 Hz, 1H),     1.38 (d, J=6.8 Hz, 3H). ES/MS 417.1 (M+H⁺); -   (S)-2-(((6-amino-5-chloropyrimidin-4-yl)amino)(cyclopropyl)methyl)-5-chloro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one     (Compound 165). ¹H NMR (400 MHz, DMSO) δ 13.16 (s, 1H), 7.86 (s,     1H), 7.84 (d, J=2.4 Hz, 1H), 7.80-7.74 (m, 1H), 7.65 (dd, J=8.2, 1.2     Hz, 1H), 7.57 (dd, J=7.8, 1.2 Hz, 1H), 7.00 (br s, 2H), 6.90 (br s,     1H), 6.39 (d, J=2.3 Hz, 1H), 4.62 (t, J=7.6 Hz, 1H), 1.41-1.32 (m,     1H), 0.42-0.36 (m, 2H), 0.30-0.19 (m, 2H). ES/MS 443.1 (M+H⁺); -   (S)-2-amino-4-((1-(5-chloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)-6-(difluoromethyl)pyrimidine-5-carbonitrile     (Compound 166). ¹H NMR (400 MHz, DMSO) δ 13.15 (br s, 1H), 7.84 (d,     J=2.4 Hz, 1H), 7.80-7.73 (m, 2H), 7.58 (td, J=7.9, 1.2 Hz, 2H), 7.55     (br s, 1H), 7.21 (br s, 1H), 6.64 (t, J=53.6 Hz, 1H), 6.52 (d, J=2.4     Hz, 1H), 4.77 (p, J=6.6 Hz, 1H), 1.41 (d, J=6.7 Hz, 3H). ES/MS 458.1     (M+H⁺); -   (S)-5-chloro-2-(1-(isothiazolo[5,4-d]pyrimidin-4-ylamino)ethyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one     (Compound 167). ¹H NMR (400 MHz, DMSO) δ 9.32 (s, 1H), 9.14 (d,     J=6.6 Hz, 1H), 8.39 (s, 1H), 7.82 (d, J=2.4 Hz, 1H), 7.71 (dd,     J=8.3, 7.8 Hz, 1H), 7.58-7.52 (m, 2H), 6.48 (d, J=2.4 Hz, 1H), 4.95     (p, J=6.8 Hz, 1H) 1.52 (d, J=6.9 Hz, 3H). ES/MS 425.1 (M+H⁺); -   (S)-2-amino-4-((1-(5-chloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)-6-(trifluoromethyl)pyrimidine-5-carbonitrile     (Compound 168). ¹H NMR (400 MHz, DMSO) δ 13.17 (s, 1H), 7.99 (d,     J=6.5 Hz, 1H), 7.87 (d, J=2.4 Hz, 1H), 7.84-7.78 (m, 2H), 7.66-7.59     (m, 2H), 7.48 (br s, 1H), 6.53 (d, J=2.4 Hz, 1H), 4.86 (p, J=6.7 Hz,     1H), 1.45 (d, J=6.7 Hz, 3H). ES/MS 476.1 (M+H⁺); -   (S)-2,4-diamino-6-((1-(6,8-difluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile     (Compound 169). ¹H NMR (400 MHz, DMSO) δ 13.24 (s, 1H), 7.94 (dd,     J=2.4, 1.6 Hz, 1H), 7.92-7.87 (m, 1H), 7.71-7.66 (m, 1H), 6.87 (d,     J=6.7 Hz, 1H), 6.62-6.53 (m, 3H), 6.30 (br s, 2H), 4.73 (p, J=6.7     Hz, 1H), 1.40 (d, J=6.7 Hz, 3H). ES/MS 425.1 (M+H⁺); -   (S)-2,4-diamino-6-((cyclopropyl(6,8-difluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)methyl)amino)pyrimidine-5-carbonitrile     (Compound 170). ¹H NMR (400 MHz, DMSO) δ 13.24 (br s, 1H), 7.97-7.89     (m, 2H), 7.69 (ddd, J=8.3, 2.9, 1.3 Hz, 1H), 6.63 (s, 2H), 6.48-6.41     (m, 2H), 6.31 (br s, 2H), 4.78 (t, J=7.3 Hz, 1H), 1.37-1.25 (m, 1H),     0.43-0.31 (m, 3H), 0.23-0.16 (m, 18). ES/MS 451.1 (M+H⁺); -   (S)-2-amino-4-(((5-chloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)(cyclopropyl)methyl)amino)-6-(difluoromethyl)pyrimidine-5-carbonitrile     (Compound 171). ¹H NMR (400 MHz, DMSO) δ 13.10 (br s, 1H), 7.82-7.75     (m, 2H), 7.63 (dd, J=8.2, 1.2 Hz, 1H), 7.59 (dd, J=7.8, 1.2 Hz, 1H),     7.54 (br s, 1H), 7.42 (d, J=7.4 Hz, 1H), 7.22 (br s, 1H), 6.63 (t,     J=53.6 Hz, 1H), 6.34 (d, J=2.4 Hz, 1H), 4.74 (t, J=7.5 Hz, 1H),     1.43-1.32 (m, 1H), 0.48-0.34 (m, 3H), 0.19-0.11 (m, 1H). ES/MS 484.1     (M+H⁺); -   (S)-2-amino-4-(((8-chloro-6-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)(cyclopropyl)methyl)amino)-6-(difluoromethyl)pyrimidine-5-carbonitrile     (Compound 172). ¹H NMR (400 MHz, DMSO) δ 13.15 (s, 1H), 8.13 (dd,     J=8.5, 2.9 Hz, 1H), 7.84-7.78 (m, 2H), 7.55 (br s, 1H), 7.37 (d,     J=7.5 Hz, 1H), 7.29 (br s, 1H), 6.64 (t, J=53.6 Hz, 1H), 6.35 (d,     J=2.4 Hz, 1H), 4.95 (t, J=7.2 Hz, 1H), 1.48-1.34 (m, 1H), 0.48-0.33     (m, 3H), 0.19-0.10 (m, 1H). ES/MS 502.1 (M+H⁺); -   (S)-2-amino-4-((1-(8-chloro-6-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)-6-(difluoromethyl)pyrimidine-5-carbonitrile     (Compound 173). ¹H NMR (400 MHz, DMSO) δ 13.19 (s, 1H), 8.11 (dd,     J=8.5, 2.9 Hz, 1H), 7.86 (d, J=2.4 Hz, 1H), 7.80 (dd, J=8.2, 2.9 Hz,     1H), 7.72 (d, J=6.6 Hz, 1H), 7.54 (br s, 1H), 7.30 (br s, 1H), 6.64     (t, J=53.6 Hz, 1H), 6.46 (d, J=2.4 Hz, 1H), 4.94 (p, J=6.6 Hz, 1H),     1.42 (d, J=6.6 Hz, 3H). ES/MS 476.1 (M+H⁺); -   (R)-8-chloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-6-fluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one     (Compound 174). ¹H NMR (400 MHz, DMSO) δ 13.27 (s, 1H), 8.19-8.14     (m, 1H), 7.93 (d, J=2.4 Hz, 1H), 7.87-7.82 (m, 1H), 7.68 (d, J=6.9     Hz, 1H), 7.44 (br s, 2H), 7.34 (br s, 2H), 6.49 (d, J=2.3 Hz, 1H),     4.91 (p, J=6.5 Hz, 1H), 1.43 (d, J=6.6 Hz, 31-H). ES/MS 450.1     (M+H⁺); -   (R)-2,4-diamino-6-((1-(8-chloro-6-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile     (Compound 175). ¹H NMR (400 MHz, DMSO) δ 13.25 (s, 1H), 8.15 (dd,     J=8.5, 2.9 Hz, 1H), 7.92 (d, J=2.4 Hz, 1H), 7.84 (dd, J=8.2, 2.9 Hz,     1H), 6.49 (d, J=2.3 Hz, 1H), 4.95 (p, J=6.6 Hz, 1H), 1.42 (d, J=6.6     Hz, 3H). ES/MS 441.1 (M+H⁺); -   (S)-2-amino-4-(difluoromethyl)-6-((1-(5-(difluoromethyl)-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile     (Compound 176). ¹H NMR (400 MHz, DMSO) δ 13.20 (s, 1H), 8.05-7.74     (m, 6H), 7.57 (br s, 1H), 7.23 (br s, 1H), 6.67 (t, J=53.5 Hz, 1H),     6.56 (d, J=2.4 Hz, 1H), 4.87 (p, J=6.6 Hz, 1H), 1.46 (d, J=6.7 Hz,     3H). ES/MS 474.1 (M+H⁺); -   (S)-2-amino-4-((cyclopropyl(5-(difluoromethyl)-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)methyl)amino)-6-(difluoromethyl)pyrimidine-5-carbonitrile     (Compound 177). ¹H NMR (400 MHz, DMSO) δ 13.20 (br s, 1H), 8.06-7.73     (m, 5H), 7.57 (br s, 1H), 7.50 (d, J=7.4 Hz, 1H), 7.23 (br s, 1H),     6.67 (t, J=53.5 Hz, 1H), 6.38 (d, J=2.3 Hz, 1H), 4.81 (t, J=7.6 Hz,     11H), 1.51-1.39 (m, 1H), 0.53-0.39 (m, 3H), 0.23-0.15 (m, 1H). ES/MS     500.1 (M+H⁺); -   (S)-2-amino-4-(difluoromethyl)-6-((1-(4-oxo-3-(1H-pyrazol-3-yl)-5-(trifluoromethyl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile     (Compound 178). ¹H NMR (400 MHz, DMSO) δ 13.21 (s, 1H), 8.05-7.95     (m, 3H), 7.88 (d, J=2.4 Hz, 1H), 7.83 (d, J=6.5 Hz, 1H), 7.58 (br s,     1H), 7.24 (br s, 1H), 6.67 (7, J=53.6 Hz, 1H), 6.57 (d, J=2.4 Hz,     1H), 4.87 (p, J=6.7 Hz, 1H), 1.46 (d, J=6.7 Hz, 3H). ES/MS 492.1     (M+H⁺); -   (S)-2-amino-4-(difluoromethyl)-6-((1-(5-(difluoromethyl)-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile     (Compound 179). ¹H NMR (400 MHz, DMSO) δ 8.08-7.74 (m, 7H), 7.57 (br     s, 1H), 7.34 (br s, 1H), 6.68 (t, J=53.5 Hz, 1H), 5.01-4.91 (m, 1H),     1.42 (d, J=6.7 Hz, 3H). ES/MS 474.1 (M+H⁺); -   (S)-2-amino-4-((1-(8-chloro-6-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)propyl)amino)-6-(difluoromethyl)pyrimidine-5-carbonitrile     (Compound 180). ¹H NMR (400 MHz, DMSO) δ 13.24 (br s, 1H), 8.14 (dd,     J=8.5, 2.9 Hz, 1H), 7.89 (d, J=2.4 Hz, 1H), 7.83 (dd, J=8.2, 2.9 Hz,     1H), 7.62 (d, J=7.1 Hz, 1H), 7.58 (br s, 1H), 7.23 (br s, 1H), 6.68     (t, J=53.5 Hz, 1H), 6.52 (d, J=2.4 Hz, 1H), 4.94-4.88 (m, 1H),     2.12-1.99 (m, 1H), 1.78 (dq, J=14.1, 7.1 Hz, 1H), 0.79 (t, J=7.3 Hz,     3H). ES/MS 490.1 (M+H⁺); -   (R)-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-5-(difluoromethyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one     (Compound 181). ¹H NMR (400 MHz, DMSO) δ 13.24 (s, 1H), 8.05-7.70     (m, 5H), 7.49 (br s, 2H), 7.34 (br s, 2H), 6.56-6.53 (m, 1H),     4.88-4.81 (m, 1H), 1.45 (d, J=6.8 Hz, 3H). ES/MS 448.1 (M+H⁺); -   (R)-2,4-diamino-6-((1-(5-(difluoromethyl)-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile     (Compound 182). ¹H NMR (400 MHz, DMSO) δ 13.25 (s, 1H), 8.18-7.73     (m, 8H), 6.54 (d, J=2.4, 1H), 4.93-4.86 (m, 1H), 1.47-1.41 (m, 3H).     ES/MS 439.1 (M+H⁺); -   (S)-2-amino-4-((1-(8-chloro-6-fluoro-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)-6-(difluoromethyl)pyrimidine-5-carbonitrile     (Compound 183). ¹H NMR (400 MHz, DMSO) δ 8.13 (dd, J=8.5, 2.9 Hz,     1H), 7.89 (br s, 2H), 7.82 (dd, J=8.2, 2.9 Hz, 1H), 7.75 (d, J=6.6     Hz, 1H), 7.58 (br s, 1H), 7.42 (br s, 1H), 6.68 (t, J=53.5 Hz, 1H),     5.02 (p, J=6.6 Hz, 1H), 1.40 (d, J=6.6 Hz, 3H). ES/MS 476.1 (M+H⁺); -   (S)-2-amino-4-(((8-chloro-6-fluoro-4-oxo     3-(1H-pyrazol-4-yl)-3,4-dihydroquinazolin-2-yl)(cyclopropyl)methyl)amino)-6-(difluoromethyl)pyrimidine-5-carbonitrile     (Compound 184). ¹H NMR (400 MHz, DMSO) δ 8.14 (dd, J=8.5, 2.9 Hz,     1H), 7.87-7.78 (m, 3H), 7.58 (br s, 1H), 7.42 (br s, 1H), 7.33 (d,     J=7.4 Hz, 1H), 6.67 (t, J=53.5 Hz, 1H), 5.06 (t, J=7.1 Hz, 1H),     1.43-1.32 (m, 1H), 0.50-0.36 (m, 3H), 0.18-0.09 (m, 1H). ES/MS 502.1     (M+H⁺); -   (S)-2-amino-4-((1-(5-chloro-8-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)-6-(difluoromethyl)pyrimidine-5-carbonitrile     (Compound 185). ¹H NMR (400 MHz, DMSO) δ 13.20 (s, 1H), 7.87 (d,     J=2.4 Hz, 1H), 7.83-7.71 (m, 2H), 7.60 (dd, J=8.8, 4.5 Hz, 1H), 7.25     (br s, 1H), 6.67 (t, J=53.5 Hz, 1H), 6.53 (d, J=2.4 Hz, 1H), 4.83     (p, J=6.7 Hz, 1H), 1.45 (d, J=6.7 Hz, 3H). ES/MS 476.1 (M+H⁺); -   (S)-2-amino-4-(difluoromethyl)-6-((1-(8-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile     (Compound 186). ¹H NMR (400 MHz, DMSO) δ 13.19 (br s, 1H), 7.97-7.93     (m, 1H), 7.87 (d, J=2.4 Hz, 1H), 7.83 (d, J=6.5 Hz, 1H), 7.77 (ddd,     J=10.5, 8.0, 1.4 Hz, 1H), 7.60-7.53 (m, 2H), 7.24 (br s, 1H), 6.67     (t, J=53.5 Hz, 1H), 6.54 (d, J=2.4 Hz, 1H), 4.88 (p, J=6.7 Hz, 1H),     1.46 (d, J=6.7 Hz, 3H). ES/MS 442.1 (M+H⁺); -   (S)-2-amino-4-((1-(6,8-difluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)-6-(difluoromethyl)pyrimidine-5-carbonitrile     (Compound 187). ¹H NMR (400 MHz, DMSO) δ 13.21 (br s, 1H), 7.92     (ddd, J=10.3, 8.9, 2.9 Hz, 1H), 7.87 (d, J=2.4 Hz, 1H), 7.82 (d,     J=6.5 Hz, 1H), 7.70 (ddd, J=8.2, 2.9, 1.2 Hz, 1H), 7.57 (br s, 1H),     7.23 (br s, 1H), 6.67 (t, J=53.5 Hz, 1H), 6.54 (d, J=2.4 Hz, 1H),     4.88 (p, J=6.7 Hz, 1H), 1.45 (d, J=6.7 Hz, 3H). ES/MS 460.1 (M+H⁺); -   (S)-2-amino-4-((1-(8-chloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)-6-(difluoromethyl)pyrimidine-5-carbonitrile     (Compound 188). ¹H NMR (400 MHz, DMSO) δ 13.22 (br s, 1H), 8.10 (dd,     J=8.0, 1.4 Hz, 1H), 8.05 (dd, J=7.9, 1.4 Hz, 1H), 7.89 (d, J=2.4 Hz,     1H), 7.77 (d, J=6.6 Hz, 1H), 7.56 (t, J=7.9 Hz, 1H), 7.34 (br s,     1H), 6.67 (t, J=53.5 Hz, 1H), 6.51 (d, J=2.4 Hz, 1H), 4.97 (p, J=6.6     Hz, 1H), 1.45 (d, J=6.6 Hz, 3H). ES/MS 458.1 (M+H⁺); -   (S)-2-amino-4-(2-(5-chloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)pyrrolidin-1-yl)-6-(difluoromethyl)pyrimidine-5-carbonitrile     (Compound 189). ¹H NMR (400 MHz, DMSO) δ 7.96 (d, J=2.3 Hz, 1H),     7.70 (t, J=8.0 Hz, 1H), 7.56-7.49 (m, 3H), 6.99-6.57 (m, 3H), 4.58     (br s, 1H), 4.10-3.92 (m, 2H), 2.26-1.88 (m, 4H). ES/MS 484.1     (M+H⁺); -   (S)-2-amino-4-((1-(5,8-dichloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)-6-(difluoromethyl)pyrimidine-5-carbonitrile     (Compound 190). ¹H NMR (400 MHz, DMSO) δ 13.23 (s, 1H), 7.99 (d,     J=8.5 Hz, 1H), 7.89 (d, J=2.3 Hz, 1H), 7.72 (d, J=6.6 Hz, 1H), 7.60     (d, J=8.5 Hz, 1H), 7.35 (br s, 1H), 6.67 (t, J=53.6 Hz, 1H),     6.51-6.48 (m, 1H), 4.97-4.89 (m, 1H), 1.44 (d, J=6.6 Hz, 3H). ES/MS     492.0 (M+H⁺); -   (S)-2-amino-4-(difluoromethyl)-6-((1-(5-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile     (Compound 191). ¹H NMR (400 MHz, DMSO) δ 13.18 (br s, 1H), 7.90-7.82     (m, 2H), 7.80 (d, J=6.4 Hz, 1H), 7.58 (br s, 1H), 7.52-7.47 (m, 1H),     7.34 (ddd, J=11.0, 8.2, 1.0 Hz, 1H), 7.23 (br s, 1H), 6.67 (t,     J=53.6 Hz, 1H), 6.55 (d, J=2.4 Hz, 1H), 4.80 (p, J=6.6 Hz, 1H), 1.44     (d, J=6.7 Hz, 3H). ES/MS 442.0 (M+H⁺); -   (S)-2-amino-4-((1-(5,8-difluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)-6-(difluoromethyl)pyrimidine-5-carbonitrile     (Compound 192). ¹H NMR (400 MHz, DMSO) δ 13.20 (s, 1H), 7.87 (d,     J=2.4 Hz, 1H), 7.84-7.75 (m, 2H), 7.58 (br s, 1H), 7.36 (ddd,     J=10.5, 9.1, 3.6 Hz, 1H), 7.24 (br s, 1H), 6.67 (t, J=53.6 Hz, 1H),     6.54 (d, J=2.4 Hz, 1H), 4.82 (p, J=6.7 Hz, 1H), 1.45 (d, J=6.7 Hz,     3H). ES/MS 460.0 (M+H⁺); -   (S)-2-amino-4-(difluoromethyl)-6-((1-(6-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile     (Compound 193). ¹H NMR (400 MHz, DMSO) δ 13.19 (br s, 1H), 7.87 (d,     J=2.4 Hz, 1H), 7.85-7.74 (m, 4H), 7.57 (br s, 1H), 7.23 (br s, 1H),     ), 6.67 (t, J=53.6 Hz, 1H), 6.55 (d, J=2.4 Hz, 1H), 4.87 (p, J=6.6     Hz, 1H), 1.45 (d, J=6.7 Hz, 3H). ES/MS 442.1 (M+H⁺); -   (S)-2-amino-4-(((5-chloro-8-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)(cyclopropyl)methyl)amino)-6-(difluoromethyl)pyrimidine-5-carbonitrile     (Compound 194). ¹H NMR (400 MHz, DMSO) δ 13.14 (br s, 1H), 7.81-7.74     (m, 2H), 7.62 (dd, J=8.8, 4.5 Hz, 1H), 7.57 (br s, 1H), 7.45 (d,     J=7.4 Hz, 1H), 7.25 (br s, 1H), 6.67 (t, J=53.6 Hz, 1H), 6.35 (d,     J=2.4 Hz, 1H), 4.79 (t, J=7.6 Hz, 1H), 1.48-1.37 (m, 1H), 0.52-0.39     (m, 3H), 0.22-0.15 (m, 1H). ES/MS 502.1 (M+H⁺); -   (S)-2-amino-4-((cyclopropyl(6,8-difluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)methyl)amino)-6-(difluoromethyl)pyrimidine-5-carbonitrile     (Compound 195). ¹H NMR (400 MHz, DMSO) δ 13.14 (br s, 1H), 7.94     (ddd, J=10.3, 9.0, 2.8 Hz, 1H), 7.79 (d, J=2.4 Hz, 1H), 7.70 (ddd,     J=8.3, 2.8, 1.3 Hz, 1H), 7.56 br (s, 1H), 7.48 (d, J=7.4 Hz, 1H),     7.23 (br s, 1H), 6.66 (t, J=53.6 Hz, 1H), 6.35 (d, J=2.4 Hz, 1H),     4.82 (t, J=7.6 Hz, 1H), 1.50-1.40 (m, 1H), 0.52-0.39 (m, 3H),     0.24-0.14 (m, 1H). ES/MS 486.1 (M+H⁺); -   (S)-2-amino-4-(((8-chloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)(cyclopropyl)methyl)amino)-6-(difluoromethyl)pyrimidine-5-carbonitrile     (Compound 196). ¹H NMR (400 MHz, DMSO) δ 13.19 (br s, 1H), 8.10 (dd,     J=8.0, 1.4 Hz, 1H), 8.07 (dd, J=7.9, 1.4 Hz, 1H), 7.84 (d, J=2.4 Hz,     1H), 7.64-7.53 (m, 2H), 7.40 (d, J=7.4 Hz, 1H), 7.33 (br s, 1H),     6.67 (t, J=53.6 Hz, 1H), 6.40 (d, J=2.4 Hz, 1H), 5.01 (t, J=7.1 Hz,     1H), 1.49-1.38 (m, 1H), 0.50-0.37 (m, 3H), 0.22-0.14 (m, 1H). ES/MS     484.1 (M+H⁺); -   (S)-4-amino-6-((1-(5-chloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)-2-(difluoromethyl)pyrimidine-5-carbonitrile     (Compound 197). ¹H NMR (400 MHz, DMSO) δ 13.18 (br s, 1H), 7.99 (d,     J=6.4 Hz, 1H), 7.89 (d, J=2.4 Hz, 1H), 7.76 (dd, J=8.2, 7.8 Hz, 1H),     7.61-7.55 (m, 2H), 6.43 (d, J=2.4 Hz, 1H), 6.37 (t, J=54.4 Hz, 1H),     4.76 (p, J=6.7 Hz, 1H), 1.44 (d, J=6.8 Hz, 3H). ES/MS 458.1 (M+H⁺); -   (S)-4-amino-6-((1-(8-chloro-6-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)-2-(difluoromethyl)pyrimidine-5-carbonitrile     (Compound 198). ¹H NMR (400 MHz, DMSO) δ 13.23 (s, 1H), 8.11 (ddd,     J=8.5, 2.9, 0.8 Hz, 1H), 7.92-7.78 (m, 3H), 7.69 (br s, 1H), 6.41     (dd, J=2.4, 0.7 Hz, 1H), 6.36 (t, J=54.4 Hz, 1H), 4.93 (p, J=6.7 Hz,     1H), 1.45 (d, J=6.8 Hz, 3H). ES/MS 476.1 (M+H⁺); -   (S)-3-(5-amino-1H-pyrazol-3-yl)-5-chloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)quinazolin-4(3H)-one     (Compound 199). ¹H NMR (400 MHz, DMSO) δ 11.81 (s, 1H), 7.81-7.75     (m, 1H), 7.64 (dd, J=8.2, 1.2 Hz, 1H), 7.59 (dd, J=7.8, 1.2 Hz, 1H),     5.49 (s, 1H), 4.95-4.86 (m, 1H), 1.46 (d, J=6.7 Hz, 3H). ES/MS 447.1     (M+H⁺); -   (S)-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-8-(difluoromethyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one     (Compound 200). ¹H NMR (400 MHz, DMSO) δ 13.25 (s, 1H), 8.30 (dd,     J=7.6, 1.3 Hz, 1H), 8.15 (d, J=7.5 Hz, 1H), 7.92 (d, J=2.4 Hz, 1H),     7.84-7.53 (m, 3H), 7.47 (br s, 2H), 7.32 (br s, 2H), 6.53 (d, J=2.3     Hz, 1H), 4.97-4.88 (m, 1H), 1.44 (d, J=6.7 Hz, 3H). ES/MS 448.1     (M+H⁺); -   (S)-2-(((2-amino-5-cyano-6-methylpyrimidin-4-yl)amino)(cyclopropyl)methyl)-3-(4-methyl-1H-pyrazol-3-yl)-4-oxo-3,4-dihydroquinazoline-8-carbonitrile     (Compound 203): ¹H NMR (400 MHz, DMSO-d₆) δ 12.69 (br s, 1H),     8.62-8.07 (m, 2H), 8.07-7.22 (m, 4H), 5.26-4.42 (m, 1H), 2.42-2.27     (m, 3H), 1.88-1.71 (m, 3H), 1.71-1.18 (m, 1H), 0.70-0.41 (m, 3H),     0.35-0.08 (m, 1H). ES/MS 453.2 (M+H⁺); -   (S)-2-(cyclopropyl((2,6-diamino-5-chloropyrimidin-4-yl)amino)methyl)-3-(4-methyl-1H-pyrazol-3-yl)-4-oxo-3,4-dihydroquinazoline-8-carbonitrile     (Compound 204): ¹H NMR (400 MHz, DMSO-d₆) δ 13.18-12.64 (m, 1H),     8.57-8.28 (m, 2H), 7.90-7.63 (m, 2H), 7.63-7.11 (m, 5H), 5.18-4.83     (m, 1H), 1.91-1.71 (m, 3H), 1.58-1.15 (m, 1H), 0.62-0.34 (m, 4H),     0.26-0.01 (m, 1H). ES/MS 463.1 (M+H⁺); -   (S)-2,4-diamino-6-((1-(4-oxo-3-(1H-pyrazol-3-yl)-5-(trifluoromethyl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile     (Compound 205): ¹H NMR (400 MHz, DMSO-d₆) δ 13.19 (s, 1H), 8.02-7.90     (m, 3H), 7.88 (d, J=2.4 Hz, 1H), 7.86-6.84 (br m, 4H), 6.53 (d,     J=2.4 Hz, 1H), 4.89-4.75 (m, 1H), 1.40 (d, J=6.7 Hz, 3H). ES/MS     457.1 (M+H⁺); -   (S)-2,4-diamino-6-((1-(4-oxo-3-(1H-pyrazol-4-yl)-5-(trifluoromethyl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile     (Compound 206): ¹H NMR (400 MHz, DMSO-d₆) δ 8.11-7.71 (m, 7H), 7.42     (br. s, 1H), 4.95 (p, J=6.8 Hz, 1H), 1.36 (d, J=6.7 Hz, 3H). ES/MS     457.1 (M+H⁺); -   (S)-2,4-diamino-6-((cyclopropyl(4-oxo-3-(1H-pyrazol-3-yl)-5-(trifluoromethyl)-3,4-dihydroquinazolin-2-yl)methyl)amino)pyrimidine-5-carbonitrile     (Compound 207): ¹H NMR (400 MHz, DMSO-d₆) δ 13.13 (br s, 1H),     8.07-7.96 (m, 4H), 7.88 (s, 2H), 7.81 (d, J=2.4 Hz, 1H), 7.79-7.67     (m, 1H), 6.35 (d, J=2.3 Hz, 1H), 4.72 (t, J=7.8 Hz, 1H), 1.50-1.36     (m, 1H), 0.53-0.33 (m, 3H), 0.22-0.11 (m, 1H). ES/MS 483.2 (M+H⁺); -   (S)-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-3-(1H-pyrazol-3-yl)-5-(trifluoromethyl)quinazolin-4(3H)-one     (Compound 208): ¹H NMR (400 MHz, DMSO-d₆) δ 13.22 (s, 1H), 8.04-7.94     (m, 3H), 7.88 (d, J=2.4 Hz, 1H), 7.73 (d, J=6.8 Hz, 1H), 7.64-7.48     (m, 2H), 7.39 (s, 2H), 6.52 (d, J=2.3 Hz, 1H), 4.82 (p, J=6.7 Hz,     1H), 1.42 (d, J=6.8 Hz, 3H). ES/MS 466.1 (M+H⁺); -   (S)-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-3-(1H-pyrazol-4-yl)-5-(trifluoromethyl)quinazolin-4(3H)-one     (Compound 209): ¹H NMR (400 MHz, DMSO-d₆) δ 7.99-7.90 (m, 3H), 7.86     (s, 2H), 7.74 (d, J=6.9 Hz, 1H), 7.53 (s, 2H), 7.43 (br. s, 2H),     4.92 (p, J=6.7 Hz, 1H), 1.37 (d, J=6.7 Hz, 3H). ES/MS 466.1 (M+H⁺); -   (S)-2-(cyclopropyl((2,6-diamino-5-chloropyrimidin-4-yl)amino)methyl)-3-(1H-pyrazol-3-yl)-5-(trifluoromethyl)quinazolin-4(3H)-one     (Compound 210): ¹H NMR (400 MHz, DMSO-d₆) δ 13.18 (br. s, 1H),     8.11-7.97 (m, 3H), 7.86 (d, J=2.4 Hz, 1H), 7.71-7.52 (m, 3H), 7.44     (s, 2H), 6.38 (d, J=2.4 Hz, 1H), 4.75 (t, J=7.8 Hz, 1H), 1.51-1.34     (m, 1H), 0.59-0.37 (m, 3H), 0.25-0.12 (m, 1H). ES/MS 492.1 (M+H⁺); -   (S)-2,4-diamino-6-((1-(5-(difluoromethyl)-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile     (Compound 211): ¹H NMR (400 MHz, DMSO-d₆) δ 13.20 (s, 1H), 8.13-7.21     (m, 1H), 6.51 (d, J=2.4 Hz, 1H), 4.91-4.79 (m, 1H), 1.41 (d, J=6.7     Hz, 31-H). ES/MS 439.2 (M+H⁺); -   (S)-2,4-diamino-6-((1-(5-(difluoromethyl)-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile     (Compound 212): ¹H NMR (400 MHz, DMSO-d₆) δ 8.04-7.79 (m, 1H),     5.02-4.90 (m, 1H), 1.36 (d, J=6.7 Hz, 3H). ES/MS 439.2 (M+H⁺); -   (S)-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-5-(difluoromethyl)-3-(1H-pyrazol-4-yl)quinazolin-4(3H)-one     (Compound 213): ¹H NMR (400 MHz, DMSO-d₆) δ 8.04-7.70 (m, 7H), 7.55     (s, 2H), 7.43 (s, 2H), 4.98-4.87 (m, 1H), 1.37 (d, J=6.7 Hz, 3H).     ES/MS 448.1 (M+H⁺); -   (S)-2,4-diamino-6-((cyclopropyl(5-(difluoromethyl)-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)methyl)amino)pyrimidine-5-carbonitrile     (Compound 214): ¹H NMR (400 MHz, DMSO-d₆) δ 13.12 (s, 1H), 8.04-7.49     (m, 9H), 6.35 (d, J=2.3 Hz, 1H), 4.72 (t, J=7.7 Hz, 1H), 1.50-1.34     (m, 1H), 0.52-0.33 (m, 3H), 0.22-0.11 (m, 1H). ES/MS 465.2 (M+H⁺); -   (S)-2-(cyclopropyl((2,6-diamino-5-chloropyrimidin-4-yl)amino)methyl)-5-(difluoromethyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one     (Compound 215): ¹H NMR (400 MHz, DMSO-d₆) δ 13.16 (s, 1H), 8.03-7.69     (m, 5H), 7.57-7.45 (m, 3H), 7.37 (s, 2H), 6.34 (d, J=2.3 Hz, 1H),     4.72 (t, J=7.8 Hz, 1H), 1.37 (dq, J=13.7, 6.9, 6.3 Hz, 1H),     0.51-0.35 (m, 3H), 0.20-0.09 (m, 1H). ES/MS 474.1 (M+H⁺); -   (S)-2,4-diamino-6-((1-(5-chloro-3-(3-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile     (Compound 216): ¹H NMR (400 MHz, DMSO-d₆) δ 8.17-7.82 (m, 3H),     7.82-7.71 (m, 1H), 7.71-7.61 (m, 1H), 7.61-7.26 (m, 2H), 5.28-4.87     (m, 1H), 2.10-1.93 (m, 3H), 1.42-1.20 (m, 3H). ES/MS 437.1 (M+H⁺); -   (S)-2,4-diamino-6-((1-(5,8-dichloro-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile     (Compound 217): ¹H NMR (400 MHz, DMSO-d₆) δ 8.03-7.59 (m, 6H), 7.95     (d, J=8.5 Hz, 1H), 7.56 (d, J=8.5 Hz, 1H), 7.40 (br. s, 2H),     5.01-4.90 (m, 1H), 1.35 (d, J=6.6 Hz, 3H). ES/MS 457.1 (M+H⁺); -   (S)-5,8-dichloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-3-(3-methyl-1H-pyrazol-4-yl)quinazolin-4(3H)-one     (Compound 218): ¹H NMR (400 MHz, DMSO-d₆) δ 13.05-12.80 (m, 1H),     8.03-7.55 (br. m, 1H), 7.96-7.90 (m, 1H), 7.57-7.49 (m, 1H),     6.62-6.28 (m, 1H), 6.11-5.94 (m, 2H), 5.81-5.50 (m, 2H), 5.00-4.82     (m, 1H), 2.17-1.91 (m, 3H), 1.36-1.12 (m, 3H). ES/MS 480.1 (M+H⁺); -   (S)-2,4-diamino-6-((1-(5,8-dichloro-3-(3-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile     (Compound 219): ¹H NMR (400 MHz, DMSO-d₆) δ 13.06-12.78 (m, 1H),     8.05-7.49 (m, 3H), 7.00-6.71 (m, 1H), 6.62 (s, 2H), 6.53-6.21 (m,     2H), 5.15-4.92 (m, 1H), 2.20-1.94 (m, 3H), 1.44-1.15 (m, 3H). ES/MS     471.1 (M+H⁺); -   (S)-2,4-diamino-6-(((8-chloro-6-fluoro-3-(3-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)(cyclopropyl)methyl)amino)pyrimidine-5-carbonitrile     (Compound 220): ¹H NMR (400 MHz, DMSO-d₆) δ 13.10-12.71 (m, 1H),     8.17-8.07 (m, 1H), 8.05-7.48 (m, 2H), 6.76-6.60 (m, 2H), 6.60-6.15     (m, 3H), 5.22-4.95 (m, 1H), 2.18-1.90 (m, 3H), 1.43-0.99 (m, 1H),     0.49-0.17 (m, 4H). ES/MS 481.1 (M+H⁺); -   (S)-8-chloro-2-(cyclopropyl((2,6-diamino-5-chloropyrimidin-4-yl)amino)methyl)-6-fluoro-3-(3-methyl-1H-pyrazol-4-yl)quinazolin-4(3H)-one     (Compound 221): ¹H NMR (400 MHz, DMSO-d₆) δ 13.25-12.75 (m, 1H),     8.18-7.58 (m, 3H), 6.36-5.98 (m, 3H), 5.85-5.48 (m, 2H), 5.31-4.85     (m, 1H), 2.16-1.90 (m, 3H), 1.31-0.93 (m, 1H), 0.44-0.15 (m, 4H).     ES/MS 490.1 (M+H⁺); -   (S)-2,4-diamino-6-((1-(8-chloro-5-methyl-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile     (Compound 222): ¹H NMR (400 MHz, DMSO-d₆) δ 13.30-13.21 (m, 1H),     7.96 (dd, J=2.4, 1.6 Hz, 1H), 7.87 (d, J=8.1 Hz, 1H), 7.32 (dd,     J=8.1, 1.0 Hz, 1H), 6.87 (d, J=7.0 Hz, 1H), 6.64 (s, 2H), 6.55 (t,     J=2.2 Hz, 1H), 6.39 (s, 2H), 4.81 (p, J=6.6 Hz, 1H), 2.70 (s, 3H),     1.38 (d, J=6.6 Hz, 3H). ES/MS 437.1 (M+H⁺); -   (S)-8-chloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-5-methyl-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one     (Compound 223): ¹H NMR (400 MHz, DMSO-d₆) δ 13.26 (t, J=2.0 Hz, 1H),     7.97 (dd, J=2.4, 1.7 Hz, 1H), 7.88 (d, J=8.1 Hz, 1H), 7.39-7.21 (m,     1H), 6.55 (t, J=2.2 Hz, 1H), 6.51 (d, J=7.5 Hz, 1H), 6.02 (s, 2H),     5.62 (s, 2H), 4.79-4.64 (m, 1H), 2.69 (s, 3H), 1.35 (d, J=6.6 Hz,     3H). ES/MS 446.1 (M+H⁺); -   (S)-2-amino-4-((1-(8-chloro-5-methyl-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)-6-(difluoromethyl)pyrimidine-5-carbonitrile     (Compound 224): ¹H NMR (400 MHz, DMSO-d₆) δ 13.21 (s, 1H), 7.94-7.85     (m, 2H), 7.74 (d, J=6.6 Hz, 1H), 7.58 (s, 1H), 7.44-7.29 (m, 2H),     6.68 (t, J=53.3 Hz, 1H), 6.51 (d, J=2.4 Hz, 1H), 4.98-4.83 (m, 1H),     2.70 (s, 3H), 1.44 (d, J=6.6 Hz, 3H). ES/MS 472.1 (M+H⁺); -   (S)-2-(1-((2-amino-5-chloro-6-(difluoromethyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one     (Compound 225): ¹H NMR (400 MHz, DMSO-d₆) δ 13.17 (s, 1H), 7.87 (dd,     J=2.4, 1.5 Hz, 1H), 7.79-7.69 (m, 1H), 7.61-7.52 (m, 2H), 7.34 (d,     J=6.7 Hz, 1H), 6.80 (t, J=53.5 Hz, 1H), 6.56 (t, J=2.1 Hz, 1H), 6.49     (br s, 2H), 4.69-4.59 (m, 1H), 1.41 (d, J=6.7 Hz, 3H). ES/MS 467.0     (M+H⁺); -   (S)-2-(1-((2-amino-5-chloro-6-(difluoromethyl)pyrimidin-4-yl)amino)ethyl)-8-chloro-6-fluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one     (Compound 226): ¹H NMR (400 MHz, DMSO-d₆) δ 13.27 (s, 1H), 8.15 (dd,     J=8.5, 2.9 Hz, 1H), 7.93 (dd, J=2.4, 1.6 Hz, 1H), 7.84 (dd, J=8.2,     2.9 Hz, 1H), 7.44 (d, J=6.8 Hz, 1H), 6.84 (t, J=53.6 Hz, 1H), 6.58     (br s, 2H), 6.54 (t, J=2.2 Hz, 1H), 4.91-4.78 (m, 1H), 1.44 (d,     J=6.7 Hz, 3H). ES/MS 485.0 (M+H⁺); -   (S)-8-chloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-5-(difluoromethyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one     (Compound 227): ¹H NMR (400 MHz, DMSO-d₆) δ 13.29 (s, 1H), 8.13 (d,     J=8.3 Hz, 1H), 7.95 (dd, J=2.3, 1.2 Hz, 1H), 7.79 (d, J=8.3 Hz, 1H),     7.78 (t, J=55.1 Hz, 1H), 6.55 (t, J=1.9 Hz, 1H), 6.40 (d, J=7.5 Hz,     1H), 6.00 (s, 2H), 5.57 (s, 2H), 4.71 (p, J=6.8 Hz, 1H), 1.35 (d,     J=6.6 Hz, 3H). ES/MS 482.1 (M+H⁺); -   (S)-2,4-diamino-6-((1-(8-chloro-5-(difluoromethyl)-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile     (Compound 228): ¹H NMR (400 MHz, DMSO-d₆) δ 13.26 (s, 1H), 8.14 (d,     J=8.2 Hz, 1H), 7.96-7.89 (m, 1H), 7.80 (d, J=8.3 Hz, 1H), 7.72 (t,     J=54.9 Hz, 1H), 6.84 (d, J=6.9 Hz, 1H), 6.58 (s, 2H), 6.53 (t, J=2.2     Hz, 1H), 6.33 (s, 1H), 4.81 (p, J=6.6 Hz, 1H), 1.37 (d, J=6.7 Hz,     3H). ES/MS 473.1 (M+H⁺); -   (S)-6-chloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-5-(difluoromethyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one     (Compound 229): ¹H NMR (400 MHz, DMSO-d₆) δ 13.28 (s, 1H), 8.46 (t,     J=53.6 Hz, 1H), 8.01 (d, J=8.8 Hz, 1H), 7.98-7.94 (m, 1H), 7.85 (d,     J=8.8 Hz, 1H), 6.61 (t, J=2.0 Hz, 1H), 6.29 (d, J=7.1 Hz, 1H), 6.00     (s, 2H), 5.55 (s, 2H), 4.65-4.54 (m, 1H), 1.39 (d, J=6.8 Hz, 3H).     ES/MS 482.1 (M+H⁺); -   (S)-2,4-diamino-6-((1-(6-chloro-5-(difluoromethyl)-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile     (Compound 230): ¹H NMR (400 MHz, DMSO-d₆) δ 13.23 (s, 1H), 8.43 (t,     J=53.6 Hz, 1H), 7.99 (d, J=8.8 Hz, 1H), 7.93-7.88 (m, 1H), 7.80 (d,     J=8.8 Hz, 1H), 6.84 (d, J=6.8 Hz, 1H), 6.64-6.52 (m, 3H), 6.28 (s,     2H), 4.65 (p, J=6.7 Hz, 1H), 1.37 (d, J=6.8 Hz, 3H). ES/MS 473.1     (M+H⁺); -   (S)-2,4-diamino-6-((1-(7,8-difluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile     (Compound 231): ¹H NMR (400 MHz, DMSO-d₆) δ 13.19 (br s, 1H),     8.00-7.89 (m, 2H), 7.88 (d, J=2.4 Hz, 1H), 7.83-7.69 (m, 2H), 7.62     (ddd, J=10.2, 9.0, 6.9 Hz, 1H), 7.40 (br s, 2H), 6.51 (d, J=2.3 Hz,     1H), 4.88-4.78 (m, 1H), 1.41 (d, J=6.8 Hz, 3H). ES/MS 425.1 (M+H⁺); -   (S)-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-7,8-difluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one     (Compound 232): ¹H NMR (400 MHz, DMSO-d₆) δ 13.23 (br s, 1H),     8.02-7.92 (m, 1H), 7.88 (d, J=2.3 Hz, 1H), 7.74 (d, J=6.7 Hz, 1H),     7.67-7.57 (m, 1H), 7.52 (s, 2H), 7.36 (s, 2H), 6.51 (d, J=2.2 Hz,     1H), 4.87-4.74 (m, 1H), 1.43 (d, J=6.7 Hz, 3H). ES/MS 434.1 (M+H⁺); -   (S)-2-(1-((2-amino-5-chloro-6-(difluoromethyl)pyrimidin-4-yl)amino)ethyl)-5,7-difluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one     (Compound 233): ¹H NMR (400 MHz, DMSO-d₆) δ 13.19 (s, 1H), 7.87 (dd,     J=2.4, 1.6 Hz, 1H), 7.40 (ddd, J=11.5, 9.5, 2.5 Hz, 1H), 7.33 (d,     J=6.5 Hz, 1H), 7.31-7.26 (m, 1H), 6.80 (t, J=53.4 Hz, 1H), 6.57 (t,     J=2.2 Hz, 1H), 6.49 (s, 2H), 4.66-4.55 (m, 1H), 1.42 (d, J=6.8 Hz,     3H). ES/MS 469.1 (M+H⁺); -   (S)-2-(1-((2-amino-5-chloro-6-(difluoromethyl)pyrimidin-4-yl)amino)ethyl)-7,8-difluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one     (Compound 234): ¹H NMR (400 MHz, DMSO-d₆) δ 13.21 (s, 1H), 7.99-7.92     (m, 1H), 7.88 (dd, J=2.4, 1.6 Hz, 1H), 7.65-7.55 (m, 1H), 7.42 (d,     J=6.6 Hz, 1H), 6.80 (t, J=53.4 Hz, 1H), 6.58 (t, J=2.2 Hz, 1H), 6.49     (s, 2H), 4.73-4.63 (m, 1H), 1.44 (d, J=6.8 Hz, 3H). ES/MS 469.1     (M+H⁺); -   (S)-2,4-diamino-6-((1-(5,7-difluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile     (Compound 235): ¹H NMR (400 MHz, DMSO-d₆) δ 13.19 (s, 1H), 7.89 (d,     J=2.4 Hz, 1H), 7.39 (ddd, J=11.5, 9.6, 2.6 Hz, 1H), 7.25 (dd, J=9.6,     2.5 Hz, 1H), 6.79 (d, J=6.6 Hz, 1H), 6.70-6.43 (m, 3H), 6.27 (s,     2H), 4.71-4.45 (m, 1H), 1.36 (d, J=6.8 Hz, 3H). ES/MS 425.1 (M+H⁺); -   (S)-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-5,7-difluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one     (Compound 236): ¹H NMR (400 MHz, DMSO-d₆) δ 13.21 (s, 1H), 7.91 (dd,     J=2.4, 1.1 Hz, 1H), 7.38 (ddd, J=11.7, 9.5, 2.5 Hz, 1H), 7.31-7.23     (m, 1H), 6.57 (t, J=1.8 Hz, 1H), 6.21 (d, J=7.2 Hz, 1H), 5.97 (s,     2H), 5.51 (s, 2H), 4.59-4.46 (m, 1H), 1.35 (d, J=6.8 Hz, 3H). ES/MS     434.1 (M+H⁺); -   (S)-2,4-diamino-6-((1-(5-chloro-7-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile     (Compound 237): ¹H NMR (400 MHz, DMSO-d₆) δ 13.18 (s, 1H), 7.89 (dd,     J=2.4, 1.6 Hz, 1H), 7.59 (dd, J=8.8, 2.6 Hz, 1H), 7.37 (dd, J=9.3,     2.6 Hz, 1H), 6.81 (br d, J=3.9 Hz, 1H), 6.59 (s, 2H), 6.57 (t, J=2.2     Hz, 1H), 6.30 (br s, 3H), 4.66-4.52 (m, 1H), 1.36 (d, J=6.8 Hz, 3H).     ES/MS 441.1 (M+H⁺); -   (S)-5-chloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-7-fluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one     (Compound 238): ¹H NMR (400 MHz, DMSO-d₆) δ 13.21 (s, 1H), 7.92 (dd,     J=2.4, 1.6 Hz, 1H), 7.58 (dd, J=8.8, 2.6 Hz, 1H), 7.40 (dd, J=9.4,     2.6 Hz, 1H), 6.58 (t, J=2.2 Hz, 1H), 6.23 (d, J=7.1 Hz, 1H), 6.00     (s, 2H), 5.55 (s, 2H), 4.58-4.48 (m, 1H), 1.34 (d, J=6.8 Hz, 3H).     ES/MS 450.0 (M+H⁺); -   (S)-2,4-diamino-6-(((5-chloro-7-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)(cyclopropyl)methyl)amino)pyrimidine-5-carbonitrile     (Compound 239): ¹H NMR (400 MHz, DMSO-d₆) δ 13.18 (s, 1H), 7.86 (dd,     J=2.4, 1.6 Hz, 1H), 7.61 (dd, J=8.8, 2.6 Hz, 1H), 7.41 (dd, J=9.2,     2.6 Hz, 1H), 6.61 (s, 2H), 6.42 (t, J=2.2 Hz, 1H), 6.35 (d, J=7.4     Hz, 1H), 6.29 (s, 2H), 4.62 (t, J=7.3 Hz, 1H), 1.32-1.20 (m, 1H),     0.42-0.13 (m, 4H). ES/MS 467.1 (M+H⁺); -   (S)-5-chloro-2-(cyclopropyl((2,6-diamino-5-chloropyrimidin-4-yl)amino)methyl)-7-fluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one     (Compound 240): ¹H NMR (400 MHz, DMSO-d₆) δ 13.23 (s, 1H), 7.91 (dd,     J=2.4, 1.6 Hz, 1H), 7.61 (dd, J=8.8, 2.6 Hz, 1H), 7.47 (dd, J=9.3,     2.6 Hz, 1H), 6.46 (t, J=2.2 Hz, 1H), 6.09 (br s, 2H), 6.01 (br d, J,     8.0 Hz, 1H), 5.62 (br s, 2H), 4.61 (dd, J=7.8, 6.8 Hz, 1H),     1.26-1.14 (m, 1H), 0.40-0.13 (m, 4H). ES/MS 476.1 (M+H⁺); -   (S)-2-(cyclopropyl((2,6-diamino-5-cyanopyrimidin-4-yl)amino)methyl)-3-(4-methyl-1H-pyrazol-3-yl)-4-oxo-3,4-dihydroquinazoline-8-carbonitrile     (Compound 241): ¹H NMR (400 MHz, DMSO-d₆) δ 13.12-12.52 (m, 1H),     8.64-8.24 (m, 2H), 8.22-6.88 (m, 8H), 5.26-4.59 (m, 1H), 1.88-1.71     (m, 3H), 1.66-1.16 (m, 1H), 0.67-0.41 (m, 3H), 0.30-0.06 (m, 1H).     ES/MS 454.2 (M+H⁺); -   2-((1     S)-((6-amino-3-bromo-3aH-pyrazolo[3,4-d]pyrimidin-4-yl)amino)(cyclopropyl)methyl)-5-chloro-3-(4-methyl-1H-pyrazol-3-yl)quinazolin-4(3H)-one     (Compound 242): ¹H NMR (400 MHz, DMSO-d₆) δ 13.61-12.71 (m, 2H),     7.89-7.71 (m, 3H), 7.68-7.47 (m, 1H), 7.46-6.45 (m, 2H), 5.32-5.05     (m, 1H), 1.92-1.71 (m, 3H), 1.34-0.93 (m, 1H), 0.47-0.26 (m, 3H),     0.24-0.02 (m, 1H). ES/MS 541.0 (M+H⁺); -   (S)-5-chloro-2-(cyclopropyl((2,6-diamino-5-chloropyrimidin-4-yl)amino)methyl)-3-(4-methyl-1H-pyrazol-3-yl)quinazolin-4(3H)-one     (Compound 248): ¹H NMR (400 MHz, DMSO-d₆) δ 13.11-12.43 (m, 1H),     7.86-7.74 (m, 2H), 7.74-7.57 (m, 2H), 7.57-7.44 (m, 2H), 7.44-7.21     (m, 3H), 4.92-4.67 (m, 1H), 1.86-1.66 (m, 3H), 1.43-1.18 (m, 1H),     0.58-0.29 (m, 3H), 0.22-0.03 (m, 1H). ES/MS 472.1 (M+H⁺); -   (S)-2-amino-4-chloro-6-(((5-chloro-3-(4-methyl-1H-pyrazol-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)(cyclopropyl)methyl)amino)pyrimidine-5-carbonitrile     (Compound 243): ¹H NMR (400 MHz, DMSO-d₆) δ 13.02-12.39 (m, 1H),     7.87-7.75 (m, 2H), 7.74-7.44 (m, 4H), 7.43-7.36 (m, 1H), 7.31-7.03     (m, 1H), 4.97-4.66 (m, 1H), 1.86-1.69 (m, 3H), 1.39 (ddd, J=69.9,     12.6, 7.4 Hz, 1H), 0.60-0.32 (m, 3H), 0.22-0.02 (m, 1H). ES/MS 482.1     (M+H⁺); -   (S)-2-amino-4-(((5-chloro-3-(4-methyl-1H-pyrazol-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)(cyclopropyl)methyl)amino)-6-methylpyrimidine-5-carbonitrile     (Compound 244): ¹H NMR (400 MHz, DMSO-d₆) δ 12.68 (br s, 1H),     8.39-7.89 (m, 1H), 7.85-7.76 (m, 1H), 7.72-7.58 (m, 2H), 7.48 (s,     2H), 7.44-7.39 (m, 1H), 4.98-4.64 (m, 1H), 2.34-2.26 (m, 3H),     1.85-1.69 (m, 3H), 1.54-1.29 (m, 1H), 0.60-0.33 (m, 3H), 0.24-0.02     (m, 1H). ES/MS 462.1 (M+H⁺); -   (S)-2,4-diamino-6-((1-(5-cyclopropyl-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile     (Compound 245): ¹H NMR (400 MHz, DMSO-d₆) δ 13.13 (br s, 1H), 7.88     (d, J=2.3 Hz, 1H), 7.85-7.72 (br m, 3H), 7.67 (t, J=7.9 Hz, 1H),     7.41 (dd, J=8.1, 1.2 Hz, 1H), 7.26 (br m, 2H), 7.07 (dt, J=7.4, 0.8     Hz, 1H), 6.54 (d, J=2.3 Hz, 1H), 4.74-4.63 (m, 1H), 3.29 (tt, J=8.5,     5.5 Hz, 1H), 1.96 (ddt, J=14.6, 11.6, 7.3 Hz, 1H), 1.86-1.62 (m,     1H), 1.04-0.84 (m, 2H), 0.84-0.59 (m, 5H). ES/MS 443.2 (M+H⁺); -   (S)-2-(((2-amino-6-chloro-5-cyanopyrimidin-4-yl)amino)(cyclopropyl)methyl)-3-(4-methyl-1H-pyrazol-3-yl)-4-oxo-3,4-dihydroquinazoline-8-carbonitrile     (Compound 246): ¹H NMR (400 MHz, DMSO-d₆) δ 12.62 (s, 1H), 8.54-8.27     (m, 2H), 7.96-7.85 (m, 1H), 7.75-7.64 (m, 1H), 7.58-7.30 (m, 2H),     7.16 (s, 1H), 5.14-4.56 (m, 1H), 1.83-1.68 (m, 3H), 1.67-1.46 (m,     1H), 0.65-0.39 (m, 3H), 0.26-0.05 (m, 1H). ES/MS 473.1 (M+H⁺); -   (S)-2,4-diamino-6-(((5-chloro-3-(4-methyl-1H-pyrazol-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)(cyclopropyl)methyl)amino)pyrimidine-5-carbonitrile     (Compound 247): ¹H NMR (400 MHz, DMSO-d₆) δ 13.11-12.43 (m, 1H),     7.87-7.71 (m, 1H), 7.71-7.56 (m, 6H), 7.56-6.92 (m, 2H), 4.96-4.66     (m, 1H), 1.86-1.70 (m, 3H), 1.48-1.15 (m, 1H), 0.59-0.27 (m, 3H),     0.24-0.03 (m, 1H). ES/MS 463.1 (M+H⁺); -   (S)-2,4-diamino-6-((1-(8-chloro-6-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile     (Compound 279). ¹H NMR (400 MHz, DMSO-d₆) δ 13.23 (d, J=2.1 Hz, 1H),     8.09 (dd, J=8.5, 2.9 Hz, 1H), 7.91 (dd, J=2.5, 1.6 Hz, 1H), 7.78     (dd, J=8.2, 2.9 Hz, 1H), 6.81 (d, J=6.9 Hz, 1H), 6.67-6.39 (m, 2H),     6.31 (s, 1H), 4.80 (p, J=6.6 Hz, 1H), 1.35 (d, J=6.6 Hz, 3H). ES/MS     441.1 (M+H⁺); -   (S)-2,4-diamino-6-((1-(5-chloro-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazolin-2-yl)butyl)amino)pyrimidine-5-carbonitrile     (Compound 249). ¹H NMR (400 MHz, DMSO-d₆) δ 13.21 (s, 1H), 8.20 (s,     1H), 7.88-7.67 (m, 2H), 7.67-7.42 (m, 2H), 6.78-6.49 (m, 3H), 6.35     (s, 1H), 4.83 (ddd, J=9.8, 7.6, 3.1 Hz, 1H), 1.86-1.57 (m, 2H), 1.27     (dd, J=15.3, 7.7 Hz, 1H), 1.04 (dq, J=14.8, 7.5 Hz, 1H), 0.61 (t,     J=7.3 Hz, 3H). ES/MS 451.1 (M+H⁺); -   (S)-5-chloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)butyl)-3-(1H-pyrazol-4-yl)quinazolin-4(3H)-one     (Compound 250). ¹H NMR (400 MHz, DMSO-d₆) δ 13.21 (s, 11H), 8.20 (d,     J=1.9 Hz, 1H), 7.90-7.65 (m, 2H), 7.59-7.36 (m, 2H), 6.02 (d, J=7.8     Hz, 3H), 5.61 (s, 2H), 4.79 (td, J=8.5, 3.6 Hz, 1H), 1.81-1.53 (m,     2H), 1.28 (dq, J=14.6, 7.2 Hz, 1H), 1.06 (dq, J=14.4, 7.4 Hz, 1H),     0.61 (t, J=7.4 Hz, 3H). ES/MS 460.1 (M+H⁺); -   (S)-2,4-diamino-6-((1-(5,8-dichloro-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazolin-2-yl)butyl)amino)pyrimidine-5-carbonitrile     (Compound 251). ¹H NMR (400 MHz, DMSO-d₆) δ 13.25 (s, 1H), 8.17 (s,     1H), 7.94 (d, J=8.5 Hz, 1H), 7.77 (s, 1H), 7.54 (d, J=8.5 Hz, 1H),     6.63 (s, 2H), 6.59-6.28 (m, 3H), 4.95 (td, J=8.3, 3.4 Hz, 1H),     1.83-1.53 (m, 2H), 1.36-1.19 (m, 1H), 1.09 (dq, J=14.5, 7.6 Hz, 1H),     0.65 (t, J=7.3 Hz, 3H). ES/MS 485.1 (M+H⁺); -   (S)-5,8-dichloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)butyl)-3-(1H-pyrazol-4-yl)quinazolin-4(3H)-one     (Compound 252). ¹H NMR (400 MHz, DMSO-d₆) δ 13.25 (s, 1H), 8.18 (d,     J=1.6 Hz, 1H), 8.04-7.84 (m, 1H), 7.82-7.67 (m, 1H), 7.53 (d, J=8.5     Hz, 1H), 6.03 (t, J=4.3 Hz, 3H), 5.64 (s, 2H), 4.90 (td, J=8.8, 3.2     Hz, 1H), 1.83-1.46 (m, 2H), 1.27 (dt. J=13.9, 6.1 Hz, 1H), 1.12 (tt,     J=14.5, 7.3 Hz, 1H), 0.65 (q, J=7.4, 6.8 Hz, 3H). ES/MS 494.0     (M+H⁺); -   (S)-2,4-diamino-6-((1-(5-chloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)butyl)amino)pyrimidine-5-carbonitrile     (Compound 253). ¹H NMR (400 MHz, DMSO-d₆) δ 13.23 (s, 1H), 7.95 (d,     J=2.5 Hz, 1H), 7.90-7.65 (m, 1H), 7.58 (dtd, J=6.6, 3.6, 3.0, 1.5     Hz, 1H), 6.78-6.47 (m, 3H), 6.24 (s, 2H), 4.77-4.44 (m, 1H),     1.98-1.59 (m, 2H), 1.42-1.17 (m, 1H), 1.08 (dq, J=14.4, 7.5 Hz, 1H),     0.66 (t, J=7.2 Hz, 3H). ES/MS 451.1 (M+H⁺); -   (S)-2,4-diamino-6-((1-(5,8-dichloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)butyl)amino)pyrimidine-5-carbonitrile     (Compound 254). ¹H NMR (400 MHz, DMSO-d₆) δ 13.27 (s, 1H), 8.04-7.77     (m, 2H), 7.67-7.40 (m, 1H), 6.80-6.51 (m, 4H), 6.30 (s, 2H), 4.83     (td, J=8.1, 3.6 Hz, 1H), 2.02-1.79 (m, 1H), 1.66 (ddt, J=17.4, 8.8,     4.5 Hz, 1H), 1.38-1.21 (m, 1H), 1.21-0.93 (m, 1H), 0.69 (t, J=7.3     Hz, 3H). ES/MS 485.1 (M+H⁺); -   (S)-5,8-dichloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)butyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one     (Compound 255). ¹H NMR (400 MHz, DMSO-d₆) δ 13.29 (s, 1H), 8.04-7.86     (m, 1H), 7.56 (dd, J=8.5, 1.3 Hz, 1H), 6.61 (q, J=2.6, 2.0 Hz, 1H),     6.24-5.87 (m, 3H), 5.54 (s, 2H), 4.90-4.42 (m, 1H), 1.85 (s, 1H),     1.73-1.49 (m, 1H), 1.28 (d, J=11.8 Hz, 1H), 1.14 (dq, J=14.8, 7.5     Hz, 1H), 0.68 (t, J=7.3 Hz, 3H). ES/MS 494.0 (M+H⁺); -   (S)-8-chloro-2-(cyclopropyl((2,6-diamino-5-chloropyrimidin-4-yl)amino)methyl)-6-fluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one     (Compound 256). ¹H NMR (400 MHz, DMSO-d₆) δ 13.32 (d, J=2.5 Hz, 1H),     8.14 (ddd, J=8.6, 3.0, 1.7 Hz, 1H), 7.98 (t, J=2.1 Hz, 1H), 7.82     (ddd, J=8.2, 3.0, 1.7 Hz, 1H), 6.52 (q, J=2.0 Hz, 1H), 6.24-5.89 (m,     3H), 5.61 (s, 2H), 4.92 (ddd, J=7.9, 5.6, 1.8 Hz, 1H), 1.25 (qd,     J=7.3, 6.6, 3.8 Hz, 1H), 0.43-0.10 (m, 4H). ES/MS 476.1 (M+H⁺); -   (S)-8-chloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)propyl)-6-fluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one     (Compound 257). ¹H NMR (400 MHz, DMSO-d₆) δ 13.31 (d, J=25.8 Hz,     1H), 8.18 (ddd, J=12.4, 8.5, 2.9 Hz, 1H), 8.02-7.77 (m, 2H), 7.59     (d, J=30.8 Hz, 2H), 7.41 (s, 2H), 6.54 (dd, J=24.8, 2.4 Hz, 1H),     4.86 (td, J=7.1, 4.6 Hz, 1H), 2.18-1.65 (m, 2H), 0.78 (dt, J=14.4,     7.3 Hz, 3H). ES/MS 464.1 (M+H⁺); -   (S)-2,4-diamino-6-((1-(8-chloro-6-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile     (Compound 258). ¹H NMR (400 MHz, DMSO-d₆) δ 13.25 (s, 1H), 8.15 (dd,     J=8.5, 2.9 Hz, 1H), 7.93 (d, J=2.4 Hz, 1H), 7.83 (dd, J=8.1, 2.9 Hz,     1H), 7.61 (s, 3H), 6.51 (d, J=2.4 Hz, 2H), 4.88 (td, J=7.1, 4.7 Hz,     1H), 2.03 (ddd, J=12.9, 7.3, 5.2 Hz, 1H), 1.77 (dt, J=14.1, 7.2 Hz,     1H), 0.78 (t, J=7.3 Hz, 3H). ES/MS 455.1 (M+H⁺); -   (S)-5-chloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-6-fluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one     (Compound 259). ¹H NMR (400 MHz, DMSO-d₆) δ 13.25 (d, J=2.2 Hz, 1H),     8.10-7.77 (m, 2H), 7.68 (dd, J=9.0, 5.0 Hz, 1H), 6.61 (t, J=2.2 Hz,     1H), 6.26 (d, J=7.3 Hz, 1H), 6.00 (s, 2H), 5.56 (s, 2H), 4.58 (q,     J=6.9 Hz, 1H), 1.37 (d, J=6.7 Hz, 3H). ES/MS 450.1 (M+H⁺); -   (S)-2,4-diamino-6-((1-(5-chloro-6-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile     (Compound 260). ¹H NMR (400 MHz, DMSO-d₆) δ 13.23 (d, J=2.1 Hz, 1H),     8.08-7.78 (m, 2H), 7.67 (dd, J=9.1, 4.9 Hz, 1H), 6.83 (d, J=6.7 Hz,     1H), 6.59 (d, J=2.2 Hz, 3H), 6.31 (s, 2H), 4.66 (p, J=6.6 Hz, 1H),     1.38 (d, J=6.8 Hz, 3H). ES/MS 441.1 (M+H⁺); -   (S)-5-chloro-2-(cyclopropyl((2,6-diamino-5-chloropyrimidin-4-yl)amino)methyl)-6-fluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one     (Compound 261). ¹H NMR (400 MHz, DMSO-d₆) δ 13.34-13.16 (m, 1H),     8.06-7.84 (m, 2H), 7.73 (dd, J=9.0, 5.0 Hz, 1H), 6.50 (t, J=2.2 Hz,     1H), 6.10-5.91 (m, 3H), 5.66-5.52 (m, 2H), 4.84-4.56 (m, 1H), 1.23     (t, J=6.8 Hz, 1H), 0.47-0.12 (m, 4H). ES/MS 476.1 (M+H⁺); -   (S)-2,4-diamino-6-(((5-chloro-6-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)(cyclopropyl)methyl)amino)pyrimidine-5-carbonitrile     (Compound 262). ¹H NMR (400 MHz, DMSO-d₆) δ 13.23 (d, J=2.2 Hz, 1H),     8.08-7.80 (m, 2H), 7.70 (dd, J=9.1, 4.9 Hz, 1H), 6.64 (s, 2H),     6.55-6.16 (m, 3H), 4.72 (t, J=7.2 Hz, 1H), 1.29 (q, J=6.5 Hz, 1H),     0.55-0.30 (m, 3H), 0.30-0.10 (m, 1H). ES/MS 467.1 (M+H⁺); -   (S)-5-chloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-6-fluoro-3-(1H-pyrazol-4-yl)quinazolin-4(3H)-one     (Compound 263). ¹H NMR (400 MHz, DMSO-d₆) δ 13.27 (d, J=21.6 Hz,     1H), 8.27-8.11 (m, 1H), 7.90 (dt, J=24.1, 9.0 Hz, 1H), 7.80-7.55 (m,     2H), 6.28 (s, 1H), 6.07 (s, 2H), 5.70 (s, 2H), 4.80 (dt, J=24.0, 6.9     Hz, 1H), 1.32 (d, J=6.8 Hz, 3H). ES/MS 450.1 (M+H⁺); -   (S)-2,4-diamino-6-((1-(5-chloro-6-fluoro-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile     (Compound 264). ¹H NMR (400 MHz, DMSO-d₆) δ 13.23 (s, 1H), 8.25-8.06     (m, 1H), 7.89 (t, J=9.0 Hz, 1H), 7.75 (d, J=1.8 Hz, 1H), 7.65 (dd,     J=9.0, 5.0 Hz, 1H), 6.80 (d, J=6.8 Hz, 1H), 6.60 (s, 2H), 6.38 (s,     2H), 4.81 (p, J=6.7 Hz, 1H), 1.33 (d, J=6.7 Hz, 3H). ES/MS 441.1     (M+H⁺). -   (S)-8-chloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-6-fluoro-3-(1H-pyrazol-4-yl)quinazolin-4(3H)-one     (Compound 265). ¹H NMR (400 MHz, DMSO-d₆) δ 13.28 (s, 1H), 8.23-8.04     (m, 2H), 7.86-7.63 (m, 2H), 6.39 (d, J=7.7 Hz, 1H), 6.03 (s, 2H),     5.68 (s, 2H), 4.98-4.73 (m, 1H), 1.32 (d, J=6.7 Hz, 3H). ES/MS 450.1     (M+H⁺); -   (S)-2,4-diamino-6-((1-(8-chloro-6-fluoro-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile     (Compound 266). ¹H NMR (400 MHz, DMSO-d₆) δ 13.26 (s, 1H), 8.11 (d,     J=8.3 Hz, 2H), 7.90-7.57 (m, 2H), 6.82 (d, J=6.9 Hz, 1H), 6.61 (s,     2H), 6.41 (s, 2H), 4.94 (h, J=6.6 Hz, 1H), 1.34 (d, J=6.6 Hz, 3H).     ES/MS 441.1 (M+H⁺); -   (S)-5-chloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)butyl)-6-fluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one     (Compound 267). ¹H NMR (400 MHz, DMSO-d₆) δ 13.26 (s, 11H), 7.97     (dd, J=2.4, 1.6 Hz, 1H), 7.87 (t, J=9.0 Hz, 1H), 7.64 (dd, J=9.1,     5.0 Hz, 1H), 6.66 (t, J=2.2 Hz, 1H), 6.26-5.85 (m, 3H), 5.52 (s,     2H), 4.82-4.49 (m, 1H), 1.98-1.53 (m, 2H), 1.30 (d, J=8.4 Hz, 1H),     1.09 (dq, J=14.5, 7.5 Hz, 1H), 0.65 (t, J=7.3 Hz, 3H). ES/MS 478.1     (M+H⁺); -   (S)-2,4-diamino-6-((1-(5-chloro-6-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)butyl)amino)pyrimidine-5-carbonitrile     (Compound 268). ¹H NMR (400 MHz, DMSO-d₆) δ 13.25 (d, J=2.4 Hz, 1H),     8.04-7.77 (m, 2H), 7.64 (dd, J=9.1, 5.0 Hz, 1H), 6.80-6.57 (m, 3H),     6.29 (s, 2H), 4.65 (td, J=8.5, 7.4, 3.3 Hz, 1H), 2.04-1.53 (m, 2H),     1.27 (dd, J=14.5, 7.3 Hz, 1H), 1.07 (tt, J=15.2, 7.7 Hz, 1H), 0.65     (t, J=7.3 Hz, 3H). ES/MS 469.1 (M+H⁺); -   (S)-2,4-diamino-6-(((8-chloro-6-fluoro-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazolin-2-yl)(cyclopropyl)methyl)amino)pyrimidine-5-carbonitrile     (Compound 269). ¹H NMR (400 MHz, DMSO-d₆) δ 13.26 (s, 1H), 8.17-7.98     (m, 2H), 7.90-7.57 (m, 2H), 6.82-6.53 (m, 2H), 6.51-6.16 (m, 3H),     5.19-4.79 (m, 1H), 1.38-1.11 (m, 1H), 0.45-0.16 (m, 3H), 0.13 (dd,     J=5.2, 3.3 Hz, 1H). ES/MS 467.1 (M+H⁺); -   (S)-3-(4-bromo-1H-pyrazol-3-yl)-8-chloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-6-fluoroquinazolin-4(3H)-one     (Compound 270). ¹H NMR (400 MHz, DMSO-d₆) δ 13.75 (s, 1H), 8.83-8.08     (m, 3H), 8.02-7.69 (m, 1H), 6.58 (dd, J=9.4, 6.2 Hz, 1H), 6.35 (d,     J=8.1 Hz, 1H), 6.03 (d, J=4.3 Hz, 2H), 5.57 (d, J=59.5 Hz, 2H),     5.02-4.65 (m, 1H), 1.40-1.13 (m, 3H). ES/MS 530.0 (M+H⁺); -   (S)-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-6-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazoline-8-carbonitrile     (Compound 271). ¹H NMR (400 MHz, DMSO-d₆) δ 13.32 (t, J=1.9 Hz, 1H),     8.49 (dd, J=8.3, 3.0 Hz, 1H), 8.15 (dd, J=8.1, 3.0 Hz, 1H), 7.98     (dd, J=2.4, 1.6 Hz, 1H), 6.57 (t, J=2.2 Hz, 1H), 6.40 (d, J=7.4 Hz,     1H), 6.02 (s, 2H), 5.59 (s, 2H), 4.75 (p, J=6.7 Hz, 1H), 1.39 (d,     J=6.7 Hz, 3H). ES/MS 441.1 (M+H⁺); -   (S)-2-(1-((2,6-diamino-5-cyanopyrimidin-4-yl)amino)ethyl)-6-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazoline-8-carbonitrile     (Compound 272). ¹H NMR (400 MHz, DMSO-d₆) δ 13.23 (s, 1H), 8.48     (ddd, J=8.5, 3.1, 0.8 Hz, 1H), 8.23-8.08 (m, 1H), 7.90 (ddd, J=3.1,     2.0, 1.0 Hz, 1H), 6.85-6.66 (m, 1H), 6.66-6.43 (m, 3H), 6.28 (s,     2H), 4.92-4.52 (m, 1H), 1.65-1.26 (m, 3H). ES/MS 432.1 (M+H⁺); -   (S)-2-(cyclopropyl((2,6-diamino-5-chloropyrimidin-4-yl)amino)methyl)-6-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazoline-8-carbonitrile     (Compound 273). ¹H NMR (400 MHz, DMSO-d₆) δ 13.34 (s, 1H), 8.50     (ddd, J=8.4, 2.9, 0.6 Hz, 1H), 8.25-8.04 (m, 1H), 7.98 (t, J=1.9 Hz,     1H), 6.59-6.35 (m, 1H), 6.26-5.93 (m, 3H), 5.60 (s, 2H), 4.91 (dd,     J=8.1, 5.8 Hz, 1H), 1.38-1.11 (m, 1H), 0.45-0.30 (m, 3H), 0.30-0.14     (m, 1H). ES/MS 467.1 (M+H⁺); -   (S)-2,4-diamino-6-((1-(4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile     (Compound 274). ¹H NMR (400 MHz, DMSO-d₆) δ 13.16 (s, 1H), 8.11     (ddd, J=8.0, 1.6, 0.6 Hz, 1H), 7.96-7.84 (m, 2H), 7.66 (ddd, J=8.1,     1.2, 0.6 Hz, 1H), 7.55 (ddd, J=8.2, 7.2, 1.2 Hz, 1H), 6.51 (d, J=2.4     Hz, 1H), 4.83 (t, J=6.7 Hz, 1H), 1.39 (d, J=6.7 Hz, 3H); -   (S)-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one     (Compound 275). ¹H NMR (400 MHz, DMSO-d₆) δ 13.18 (s, 1H), 8.11     (ddd, J=7.9, 1.6, 0.6 Hz, 1H), 7.93-7.79 (m, 2H), 7.76-7.65 (m, 2H),     7.56 (ddd, J=7.9, 7.2, 1.2 Hz, 1H), 7.47 (s, 2H), 7.33 (s, 2H), 6.51     (d, J=2.4 Hz, 1H), 4.81 (t, J=6.8 Hz, 1H), 1.41 (d, J=6.7 Hz, 3H); -   (S)-8-chloro-2-(cyclopropyl((2,6-diamino-5-chloropyrimidin-4-yl)amino)methyl)-6-fluoro-3-(1H-imidazol-4-yl)quinazolin-4(3H)-one     (Compound 280): ¹H NMR (400 MHz, DMSO-d₆) δ 12.52 (s, 1H), 8.10 (dd,     J=8.5, 2.9 Hz, 1H), 7.86-7.68 (m, 2H), 7.45-7.33 (m, 1H), 6.17 (d,     J=5.3 Hz, 1H), 6.04 (s, 2H), 5.65 (s, 2H), 4.96 (dd, J=8.0, 5.6 Hz,     1H), 1.36-1.21 (m, 1H), 0.34-0.13 (m, 4H). ES/MS 476.1 (M+H⁺); -   (S)-2,4-diamino-6-(((8-chloro-6-fluoro-3-(1H-imidazol-4-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)(cyclopropyl)methyl)amino)pyrimidine-5-carbonitrile     (Compound 281): ¹H NMR (400 MHz, DMSO-d₆) δ 12.51 (s, 1H), 8.10 (dd,     J=8.5, 2.9 Hz, 1H), 7.89-7.70 (m, 2H), 7.36 (dd, J=2.2, 1.3 Hz, 1H),     6.62 (s, 2H), 6.45 (d, J=7.7 Hz, 1H), 6.38 (s, 2H), 5.01 (dd, J=7.7,     6.0 Hz, 1H), 1.38-1.24 (m, 1H), 0.39-0.21 (m, 3H), 0.21-0.11 (m,     1H). ES/MS 467.1 (M+H⁺); -   (S)-5-chloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)butyl)-3-(1H-imidazol-4-yl)quinazolin-4(3H)-one     (Compound 282): ¹H NMR (400 MHz, DMSO-d₆) δ 12.46 (s, 1H), 7.80 (d,     J=1.3 Hz, 1H), 7.70 (dd, J=8.3, 7.8 Hz, 1H), 7.57-7.48 (m, 3H), 6.18     (s, 1H), 6.10 (s, 2H), 5.72 (s, 2H), 4.73-4.64 (m, 1H), 1.90-1.77     (m, 1H), 1.72-1.59 (m, 1H), 1.32-1.18 (m, 1H), 1.13-0.99 (m, 1H),     0.63 (t, J=7.3 Hz, 3H). ES/MS 460.1 (M+H⁺); -   (S)-2,4-diamino-6-((1-(5-chloro-3-(1H-imidazol-4-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)butyl)amino)pyrimidine-5-carbonitrile     (Compound 283): ¹H NMR (400 MHz, DMSO-d₆) δ 12.45 (s, 1H), 7.79 (t,     J=1.3 Hz, 1H), 7.71 (dd, J=8.3, 7.8 Hz, 1H), 7.57-7.48 (m, 3H), 6.67     (d, J=7.6 Hz, 1H), 6.56 (s, 2H), 6.31 (s, 2H), 4.74 (ddd, J=9.5,     7.6, 3.3 Hz, 1H), 1.91-1.77 (m, 1H), 1.70 (ddp, J=13.6, 9.1, 4.6 Hz,     1H), 1.31-1.17 (m, 1H), 1.11-0.96 (m, 1H), 0.63 (t, J=7.3 Hz, 3H).     ES/MS 451.2 (M+H⁺); -   (S)-8-chloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-6-fluoro-3-(1H-imidazol-4-yl)quinazolin-4(3H)-one     (Compound 284): ¹H NMR (400 MHz, DMSO-d₆) δ 12.52 (s, 1H), 8.08 (dd,     J=8.5, 2.9 Hz, 1H), 7.81 (t, J=1.2 Hz, 1H), 7.77 (dd, J=8.2, 2.9 Hz,     1H), 7.47 (dd, J=2.2, 1.4 Hz, 1H), 6.38 (d, J=7.5 Hz, 1H), 5.97 (s,     2H), 5.61 (s, 2H), 4.85-4.70 (m, 1H), 1.34 (d, J=6.7 Hz, 3H). ES/MS     450.1 (M+H⁺); -   (S)-2,4-diamino-6-((1-(8-chloro-6-fluoro-3-(1H-imidazol-4-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile     (Compound 285): ¹H NMR (400 MHz, DMSO-d₆) δ 12.51 (s, 1H), 8.08 (dd,     J=8.5, 2.9 Hz, 1H), 7.85-7.68 (m, 2H), 7.45 (t, J=1.6 Hz, 1H), 6.81     (d, J=6.9 Hz, 1H), 6.57 (s, 2H), 6.37 (s, 2H), 4.96-4.79 (m, 1H),     1.36 (d, J=6.7 Hz, 3H). ES/MS 441.1 (M+H⁺); -   (S)-2,4-diamino-6-((1-(5,8-dichloro-3-(1H-imidazol-4-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile     (Compound 286): ¹H NMR (400 MHz, DMSO-d₆) δ 12.51 (s, 1H), 7.93 (d,     J=8.5 Hz, 1H), 7.80 (d, J=1.3 Hz, 1H), 7.54 (d, J=8.5 Hz, 1H), 7.44     (d, J=1.4 Hz, 1H), 6.84 (br. d, J=6.9 Hz, 1H), 6.63 (s, 2H), 6.42     (s, 2H), 4.89-4.77 (m, 1H), 1.36 (d, J=6.6 Hz, 3H). ES/MS 457.1     (M+H⁺); -   (S)-2,4-diamino-6-((1-(5-chloro-4-oxo-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile.     ES/MS 553.2 (M+H⁺); -   (S)-5-chloro-2-(cyclopropyl((2,6-diamino-5-chloropyrimidin-4yl)amino)methyl)-3-(1H-imidazol-4-yl)quinazolin-4(3H)-one     (Compound 287): ¹H NMR (400 MHz, DMSO-d₆) δ 12.56 (s, 1H), 7.82-7.74     (m, 2H), 7.66 (dd, J=8.2, 1.2 Hz, 1H), 7.59 (dd, J=7.8, 1.2 Hz, 1H),     7.57-7.29 (m, 6H), 7.27 (d, J=1.3 Hz, 1H), 4.74 (t, J=7.7 Hz, 1H),     1.41-1.17 (m, 1H), 0.49-0.30 (m, 3H), 0.21-0.11 (m, 1H). ES/MS 458.1     (M+H⁺); -   (S)-2,4-diamino-6-((1-(5-chloro-4-oxo-3-(1H-pyrrol-2-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile     (Compound 289). ¹H NMR (400 MHz, DMSO) δ 11.27-11.12 (m, 1H),     7.81-7.69 (m, 1H), 7.60-7.48 (m, 2H), 6.93-6.84 (m, 1H), 6.26-6.09     (m, 1H), 1.45-1.25 (m, 3H). ES/MS 422.1 (M+H⁺); -   (S)-5-chloro-3-(1H-pyrrol-2-yl)-2-(1-(thiazolo[5,4-d]pyrimidin-7-ylamino)ethyl)quinazolin-4(3H)-one     (Compound 290). ¹H NMR (400 MHz, DMSO) δ 11.20 (br s, 1H), 9.29 (s,     1H), 8.42 (s, 1H), 8.38 (s, 1H), 7.71 (dd, J=8.3, 7.7 Hz, 1H),     7.57-7.52 (m, 2H), 6.90-6.86 (m, 1H), 6.27-6.22 (m, 1H), 6.15-6.11     (m, 1H), 5.06 (br s, 1H), 1.45 (br s, 3H). ES/MS 424.1 (M+H⁺); and -   (S)-5-chloro-2-(1-(imidazo[2,1-f][1,2,4]triazin-4-ylamino)ethyl)-3-(1H-pyrrol-2-yl)quinazolin-4(3H)-one     (Compound 291). ¹H NMR (400 MHz, DMSO) δ 11.20 (br s, 1H), 8.93 (d,     J=6.4 Hz, 1H), 8.12 (s, 1H), 8.05 (d, J=1.1 Hz, 1H), 7.71 (dd,     J=8.3, 7.7 Hz, 1H), 7.61 (d, J=1.1 Hz, 1H), 7.57-7.54 (m, 1H),     7.54-7.52 (m, 1H), 6.87 (td, J=2.8, 1.7 Hz, 1H), 6.25-6.20 (m, 1H),     6.14-6.10 (m, 1H), 4.76 (br s, 1H), 1.45 (br s, 3H). ES/MS 407.1     (M+H⁺).

C. Preparation of a compound of formula (I), where X is CH, Y is N, Z is C and the attachment point with the quinazolinone, A is CO, n is 1, R¹ is Cl, m′ is 0, R³ is methyl, R⁵ is hydrogen, and R⁴ is 2-aminopyrazolo[1,5-a]pyrimidin-3-yl

Trifluoroacetic acid (0.5 mL) was added to a suspension of(S)-tert-butyl (1-(5-chloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)carbamate (120 mg, 0.31 mmol) in dichloromethane (2.0 mL). The solution was stirred at room temperature for 3 hours and concentrated in vacuo. Dichloromethane (3.5 mL) was then added and the resulting solution was transferred to a flask containing 2-aminopyrazolo[1,5-a]pyrimidine-3-carboxylic acid (60 mg, 0.34 mmol). Diisopropylethylamine (0.32 mL, 1.8 mmol) and HATU (176 mg, 0.46 mmol) were then added and the reaction mixture was stirred at room temperature for 16 hours. The reaction was concentrated and a DMSO solution of the crude mixture was then purified by HPLC eluting with 5%-95% water/acetonitrile (0.1% v/v trifluoroacetic acid). The appropriate fractions were pooled and lyophilized to afford (S)-2-amino-N-(1-(5-chloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound 117). ¹H NMR (400 MHz, DMSO) δ 13.31 (br s, 1H), 8.92 (dd, J=6.7, 1.7 Hz, 1H), 8.77 (d, J=7.6 Hz, 1H), 8.65 (dd, J=4.5, 1.7 Hz, 1H), 8.00 (d, J=2.4 Hz, 1H), 7.87-7.75 (m, 1H), 7.72 (dd, J=8.2, 1.3 Hz, 1H), 7.61 (dd, J=7.8, 1.2 Hz, 1H), 7.02 (dd, J=6.7, 4.5 Hz, 1H), 6.51 (d, J=2.3 Hz, 1H), 4.88-4.74 (m, 1H), 1.39 (d, J=6.7 Hz, 3H). ES/MS 450.1 (M+H⁺).

D. Preparation of the below compound of formula (I) using the methods described in Example 4C and Reaction Scheme I:

-   (S)-3-amino-N-(1-(5,8-dichloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)propyl)pyrazine-2-carboxamide     (Compound 118). ¹H NMR (400 MHz, DMSO) δ 8.98 (d, J=8.4 Hz, 1H),     8.24 (d, J=2.4 Hz, 1H), 8.02-7.98 (m, 2H), 7.88 (d, J=2.4 Hz, 1H),     7.59 (d, J=8.5 Hz, 1H), 6.47 (d, J=2.3 Hz, 1H), 4.75 (td, J=8.0, 4.2     Hz, 1H), 2.03-1.92 (m, 1H), 1.73-1.60 (m, 1H), 0.77 (t, J=7.3 Hz,     3H). ES/MS 459.0 (M+H⁺); -   (S)—N-(1-(5,8-dichloro-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazolin-2-yl)propyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide     (Compound 119). ¹H NMR (400 MHz, DMSO) δ 9.34 (dd, J=7.0, 1.6 Hz,     1H), 8.97 (d, J=8.4 Hz, 1H), 8.86 (dd, J=4.2, 1.7 Hz, 1H), 8.57 (s,     1H), 7.97 (d, J=8.5 Hz, 1H), 7.91 (s, 1H), 7.57 (d, J=8.5 Hz, 1H),     7.30 (dd, J=7.0, 4.2 Hz, 1H), 5.06 (td, J=7.9, 4.2 Hz, 1H),     1.99-1.87 (m, 1H), 1.69-1.60 (m, 1H), 0.81 (t, J=7.3 Hz, 3H). ES/MS     483.0 (M+H⁺); -   (S)—N-(1-(5,8-dichloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)propyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide     (Compound 120). ¹H NMR (400 MHz, DMSO) δ 9.34 (dd, J=7.0, 1.7 Hz,     1H), 8.98 (d, J=8.4 Hz, 1H), 8.86 (dd, J=4.2, 1.7 Hz, 1H), 8.55 (s,     1H), 8.03 (d, J=2.3 Hz, 1H), 7.99 (d, J=8.5 Hz, 1H), 7.59 (d, J=8.5     Hz, 1H), 7.30 (dd, J=7.0, 4.2 Hz, 1H), 4.92 (td, J=8.1, 4.0 Hz, 1H),     2.02-1.93 (m, 1H), 1.71-1.60 (m, 1H), 0.80 (t, J=7.4 Hz, 3H). ES/MS     483.1 (M+H⁺); -   (S)-3-amino-N-(1-(5-chloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)pyrazine-2-carboxamide     (Compound 121). ¹H NMR (400 MHz, DMSO) δ 8.94 (d, J=7.6 Hz, 1H),     8.25 (d, J=2.3 Hz, 1H), 7.98 (d, J=2.4 Hz, 1H), 7.88 (d, J=2.3 Hz,     1H), 7.84-7.77 (m, 1H), 7.68 (dd, J=8.2, 1.2 Hz, 1H), 7.61 (dd,     J=7.8, 1.2 Hz, 1H), 6.48 (d, J=2.3 Hz, 1H), 4.79-4.68 (m, 1H), 1.40     (d, J=6.7 Hz, 3H). ES/MS 411.1 (M+H⁺); and -   (S)-3-amino-N-(1-(5,8-dichloro-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazolin-2-yl)propyl)pyrazine-2-carboxamide     (Compound 122). ¹H NMR (400 MHz, DMSO) δ 9.01 (d, J=8.3 Hz, 1H),     8.24 (d, J=2.4 Hz, 1H), 7.98 (d, J=8.5 Hz, 1H), 7.89-7.83 (m, 3H),     7.58 (d, J=8.5 Hz, 1H), 4.85 (td, J=7.9, 4.5 Hz, 1H), 1.99-1.88 (m,     1H), 1.73-1.62 (m, 1H), 0.79 (t, J=7.3 Hz, 3H). ES/MS 459.0 (M+H⁺). -   (S)-3,5-diamino-6-chloro-N-(1-(5-chloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)pyrazine-2-carboxamide     (Compound 276): 1H NMR (400 MHz, DMSO) δ 13.25 (t, J=1.9 Hz, 1H),     8.14 (d, J=7.5 Hz, 1H), 7.94 (dd, J=2.4, 1.6 Hz, 1H), 7.84-7.69 (m,     1H), 7.69-7.49 (m, 2H), 7.07 (s, 3H), 6.43 (t, J=2.2 Hz, 1H), 4.61     (dd, J=7.5, 6.7 Hz, 1H), 1.32 (d, J=6.7 Hz, 3H); -   (S)-3,5-diamino-6-chloro-N-(1-(5-chloro-8-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)pyrazine-2-carboxamide     (Compound 277): ¹H NMR (400 MHz, DMSO-d₆) δ 13.32 (s, 1H), 8.27 (d,     J=7.5 Hz, 1H), 7.98 (dd, J=2.4, 0.6 Hz, 1H), 7.77 (ddd, J=9.6, 8.9,     0.7 Hz, 1H), 7.67-7.53 (m, 1H), 7.11 (s, 2H), 6.47 (dd, J=2.4, 0.6     Hz, 1H), 4.75-4.57 (m, 1H), 1.44-1.30 (m, 3H); and -   (S)-3,5-diamino-6-chloro-N-(1-(5-chloro-8-fluoro-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazolin-2-yl)ethyl)pyrazine-2-carboxamide     (Compound 278): ¹H NMR (400 MHz, DMSO-d₆) δ 8.31 (d, J=7.3 Hz, 1H),     7.86 (s, 2H), 7.75 (dd, J=9.6, 8.7 Hz, 1H), 7.59 (dd, J=8.8, 4.4 Hz,     1H), 7.10 (s, 2H), 4.85-4.73 (m, 1H), 1.33 (d, J=6.7 Hz, 3H),     1.29-1.19 (m, 2H).

E. Preparation of a compound of formula (I) where X is CH, Y is N, Z is C and the attachment point with the quinazolinone, A is a single bond, n is 1, R¹ is chloro, m′ is 0, R³ is CH₃, R⁵ is hydrogen, and R is 2,6-diamino-5-trifluoromethylpyrimidin-4-yl

To a solution of (S)-5-chloro-2-(1-((2,6-diaminopyrimidin-4-yl)amino)ethyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one (100 mg, 0.251 mmol) and Na₂SO₂CF₃ (118 mg, 0.754 mmol) in dichloromethane (1.0 mL) and water (0.4 mL) at 0° C. was added tert-butylhydroperoxide (70% solution in water, 0.17 mL, 1.25 mmol). The mixture was stirred at room temperature overnight and diluted with dichloromethane, washed with water, and dried over magnesium sulfate. The organic layer was filtered and concentrated in vacuo. A DMSO solution of the crude mixture was then purified by HPLC eluting with 5%-95% water/acetonitrile (0.1% v/v trifluoroacetic acid). The appropriate fractions were pooled and lyophilized to afford (S)-5-chloro-2-(1-((2,6-diamino-5-(trifluoromethyl)pyrimidin-4-yl)amino)ethyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one (Compound 201). ¹H NMR (400 MHz, DMSO) δ 13.24 (s, 1H), 7.93 (d, J=2.4 Hz, 1H), 7.78 (t, J=8.0 Hz, 1H), 7.58 (td, J=7.8, 1.2 Hz, 2H), 6.51 (br s, 1H), 4.85, 4.77 (m, 1H), 1.35 (d, J=6.6 Hz, 3H). ES/MS 466.1 (M+H⁺);

F. Preparation of a compound of formula (1) where X is CH, Y is N, Z is C and the attachment point with the quinazolinone, A is a single bond, n is 1, R¹ is chloro, m′ is 0, R³ is CH₃, R⁵ is hydrogen, and R⁴ is 5-cyanothieno[2,3-d]pyrimidin-4-yl

(S)-2-(1-((5-bromothieno[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-chloro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one (55 mg, 0.11 mmol), zinc cyanide (15 mg, 0.13 mmol), and tetrakis(triphenylphosphine)palladium(0) (19 mg, 0.016 mmol) were combined in NMP and degassed under argon. The resulting solution was heated to 120° C. in the microwave for 2 hours. The reaction was cooled to room temperature and filtrated. The solution of the crude mixture was then purified by HPLC eluting with 5%-95% water/acetonitrile (0.1% v/v trifluoroacetic acid). The appropriate fractions were pooled and lyophilized to afford (S)-4-((1-(5-chloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)thieno[2,3-d]pyrimidine-5-carbonitrile (Compound 202). ¹H NMR (400 MHz, DMSO) δ 13.36 (s, 1H), 8.82 (s, 1H), 8.49 (s, 1H), 8.02 (d, J=2.4 Hz, 1H), 7.98 (d, J=6.6 Hz, 1H), 7.86 (t, J=8.0 Hz, 1H), 7.74 (dd, J=8.1, 1.2 Hz, 1H), 7.63 (dd, J=7.9, 1.2 Hz, 1H), 6.55 (d, J=2.3 Hz, 1H), 5.11 (p, J=6.5 Hz, 1H), 1.44 (d, J=6.5 Hz, 3H). ES/MS 449.1 (M+H⁺);

G. Preparation of a compound of formula (I) where Y is CH, Z is N, X is C and the attachment point with the quinazolinone, A is a single bond, n is 1, R¹ is chloro, m′ is 0, R³ is CH₃, R⁵ is hydrogen, and R⁴ is 2,6-diamino-5-cyanopyrimidin-4-yl

To a solution of (S)-2,4-diamino-6-((1-(5-chloro-4-oxo-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (13 mg, 0.024 mmol) in DCM (1 mL) was added several drops of TFA. The mixture was allowed to stir at ambient temperature for 18 hours, then was concentrated in vacuo and purified by prep LC to give (S)-2,4-diamino-6-((1-(5-chloro-3-(1H-imidazol-4-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (Compound 288): ¹H NMR (400 MHz, DMSO-d₆) δ 12.62 (br s, 1H), 7.87 (s, 1H), 7.81-7.72 (m, 1H), 7.60-7.54 (m, 2H), 7.47 (d, J=1.4 Hz, 1H), 4.86-4.76 (m, 1H), 1.38 (d, J=6.7 Hz, 3H). ES/MS 423.1 (M+H⁺).

Example 5 Preparation of Compounds of Formula (B)

A. Preparation of a compound of formula (B) where n is 1, and R¹ is difluoromethyl

To a solution of 2-methyl-6-nitrobenzoic acid (15 g, 82.8 mmol) in dichloromethane (150 mL) and tert-butanol (150 mL) were added di-tert-butyldicarbonate (36.1 g, 165.6 mmol) and DMAP (3.0 g, 24.8 mmol). The mixture was stirred at room temperature for 20 hours. The mixture was diluted with EtOAc (750 mL) and quenched with aqueous 1N HCl (750 mL). The phases were separated and the organic phase was washed with saturated aqueous NaHCO₃ (750 mL), brine (500 mL), and dried over magnesium sulfate. The organic layer was filtered and concentrated in vacuo to afford tert-butyl 2-methyl-6-nitrobenzoate.

To a solution of tert-butyl 2-methyl-6-nitrobenzoate (14.8 g, 62.4 mmol) in CCl₄ (230 mL) were added NBS (12.2 g, 68.6 mmol) and benzoyl peroxide (1.51 g, 6.2 mmol). The mixture was stirred at reflux temperature for 20 hours. The mixture was concentrated and purified by column chromatography on SiO₂ eluting with EtOAc in hexanes (0-30%) to afford tert-butyl 2-(bromomethyl)-6-nitrobenzoate.

To a solution of tert-butyl 2-(bromomethyl)-6-nitrobenzoate (14.2 g, 44.9 mmol) in acetonitrile (300 mL) at 0° C. was added N-methylmorpholine oxide (6.3 g, 53.9 mmol). The mixture was stirred at room temperature for 20 hours. The mixture was concentrated and purified by column chromatography on SiO₂ eluting with EtOAc in hexanes (5-40%) to afford tert-butyl 2-formyl-6-nitrobenzoate.

To a solution of tert-butyl 2-formyl-6-nitrobenzoate (3.8 g, 15.1 mmol) in DCM (75 mL) at 0° C. was added DAST (4.0 mL, 30.2 mmol). The mixture was stirred at room temperature for 20 hours. The mixture was quenched with water, the phases were separated, and the aqueous phases was extracted with DCM (2×). The combined organic phases were washed with brine and dried over magnesium sulfate. The organic layer was filtered, concentrated in vacuo, and purified by column chromatography on SiO₂ eluting with EtOAc in hexanes (0-30%) to afford tert-butyl 2-(difluoromethyl)-6-nitrobenzoate.

To a solution of tert-butyl 2-(difluoromethyl)-6-nitrobenzoate (3.6 g, 13.2 mmol) in DCM (65 mL) was added TFA (15 mL). The mixture was stirred at room temperature for 20 hours and concentrated in vacuo to afford 2-(difluoromethyl)-6-nitrobenzoic acid.

To a solution of 2-(difluoromethyl)-6-nitrobenzoic acid (2.8 g, 13.2 mmol) in ethyl acetate (65 mL) was added 10% Pd/C (1.4 g). The mixture was stirred under a hydrogen balloon at room temperature for 20 hours. The mixture was filtered over Celite® and concentrated in vacuo to afford 2-amino-6-(difluoromethyl)benzoic acid.

B. Preparation of the below compounds of formula (B) using the methods described in Example 5A:

-   2-amino-3-(difluoromethyl)benzoic acid; and -   2-amino-3-(difluoromethyl)-5-fluorobenzoic acid.

Biological Examples

The compounds of formula (I) were characterized for their enzymatic activity against the PI3K isoforms. The activities were measured using a time-resolved fluorescence resonance energy transfer (TR-FRET) assay. TR-FRET monitored the formation of 3,4,5-inositol triphosphate molecule that competed with fluorescently labeled PIP3 for binding to the GRP-1 pleckstrin homology domain protein. An increase in phosphatidylinositide 3-phosphate product resulted in a decrease in TR-FRET signal as the labeled fluorophore was displaced from the GRP-1 protein binding site.

Class 1 PI3K isoforms were expressed and purified as heterodimeric recombinant proteins. All assay reagents and buffers for the TR-FRET assay were purchased from Millipore. PI3K isoforms were assayed under initial rate conditions in the presence of 25 mM Hepes (pH 7.4), and 2× Km ATP (75-500 μM), 2 μM PIP2, 5% glycerol, 5 mM MgCl₂, 50 mM NaCl, 0.05% (v/v) Chaps, 1 mM dithiothreitol, and 1% (v/v) DMSO at the following concentrations for each isoform: PI3Kα, PI3Kβ, and PI3Kδ between 25 and 50 pM, and PI3Kγ at 2 nM. The compounds of Table 1 and Compound X ((S)-2,4-diamino-6-((1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile) were added to the assay solution and incubated for 30 minutes at 25° C. The reactions were terminated with a final concentration of 10 mM EDTA, 10 nM labeled-PIP3, and 35 nM Europium labeled GRP-1 detector protein before reading TR-FRET on an Envision plate reader (Ex: 340 nm; Em: 615/665 nm; 100 μs delay and 500 μs read window).

The results were normalized based on positive (1 μM wortmanin) and negative (DMSO) controls, and the IC₅₀ values for PI3Kα, β, δ, and γ were calculated from the fit of the dose-response curves to a four-parameter equation. These assays generally produced results within 3-fold of the reported mean.

Table 2 summarizes the IC₅₀ (nM) values for PI3K isoforms β, δ, and γ. The results indicate that certain compounds of formula (I) inhibit both PI3Kδ and PI3Kβ. Also, Compound X exhibited PI3Kδ IC₅₀ of 0.2 nM, PI3Kβ IC₅₀ of 11 nM, PI3Kγ IC₅₀ of 7 nM. The PI3Kγ/PI3Kβ ratio for Compound X is 0.6. The results indicate that certain compounds have greater selectivity for PI3Kβ over PI3Kγ compared to compound X. Compounds of Table 1a were analyzed using the same assay, and the results are summarized in Table 2a.

TABLE 2 The IC₅₀ values (nM) for PI3K isoforms β, δ, and γ. Compound PI3Kβ PI3Kδ PI3Kγ 1 1 0.6 330 2 14 3 990 3 55 2 3000 4 84 7 >10000 5 340 28 >10000 6 730 150 >10000 7 200 43 >10000 8 41 11 >10000 9 940 140 >10000 10 71 28 >10000 11 120 44 >10000 12 220 51 >10000 13 140 39 >10000 14 350 51 7600 15 1 0.4 43 16 0.8 0.2 51 17 2 0.6 67 18 2 0.5 190 19 32 6 1700 20 15 5 5900 21 9 2 230 22 2 0.6 990 23 150 9 740 24 22 4 780 25 5 1 130 26 3 0.6 1300 27 2 0.7 71 28 2 0.8 270 29 3 6 440 30 2 3 1300 31 1 1 160 32 1 1 600 33 84 22 2000 34 7 8 6100 35 21 10 1400 36 2 5 4100 37 1 0.6 5100 38 9 4 1100 39 170 22 4700 40 280 38 8700 41 88 13 1600 42 77 10 460 43 39 9 >10000 44 84 10 >10000 45 15 4 >10000 46 18 4 >10000 47 11 11 2400 48 9 8 >10000 49 150 9 3500 50 47 7 1800 51 9 2 >10000 52 70 6 >10000 53 76 13 >10000 54 240 18 >10000 55 570 65 >10000 56 1300 88 >10000 57 380 29 >10000 58 320 14 5900 59 97 2 >10000 60 43 2 >10000 61 20 3 8100 62 120 9 >10000 63 5 6 1300 64 2 2 1200 65 18 9 4200 66 150 36 >10000 67 3 3 2800 68 44 20 >10000 69 13 6 >10000 70 30 14 >10000 71 38 13 >10000 72 4 0.5 4000 73 95 18 >10000 74 20 5 >10000 75 1 3 5100 76 0.6 2 6300 77 140 5 1700 78 190 53 >10000 79 650 340 9000 80 22 35 >10000 81 12 16 >10000 82 4700 4100 >10000 83 13 1 240 84 8 0.4 93 85 170 4 9000 86 340 19 >10000 87 70 0.4 8200 88 4200 2700 >10000 89 3100 1900 >10000 90 1800 830 >10000 91 3600 2400 >10000 92 10 6 3800 93 16 9 3800 94 100 8 1500 95 1700 300 >10000 96 22 12 >10000 97 17 16 3700 98 0.3 0.6 110 99 0.8 1 93 100 22 4 280 101 1 0.5 960 102 82 29 2500 103 620 100 8700 104 61 2 500 105 5 3 680 106 4 2 210 107 49 11 2400 108 5 1 150 109 25 9 4900 110 4 1 410 111 42 10 >10000 112 17 4 2200 113 2 1 980 114 110 23 >10000 115 2 1 560 116 210 44 >10000 117 37 110 160 118 510 260 >10000 119 360 170 7200 120 530 720 >10000 121 79 20 890 122 640 200 >10000 123 10 5 >10000 124 14 12 6700 125 0.7 0.6 630 126 5 3 2800

TABLE 2a The IC₅₀ values (nM) for PI3K isoforms β, δ, and γ. Compound PI3Kβ PI3Kδ PI3Kγ 127 49 21 >10000 128 2 2 2000 129 270 86 >10000 130 4 4 7800 131 2 4 2000 132 75 42 >10000 133 2 3 474 134 37 24 9300 135 2 1 340 136 9 11 5500 137 4 9 >10000 138 46 140 9300 139 33 21 >10000 140 2 5 6080 141 130 110 >10000 142 35 47 >10000 143 2 3 7500 144 130 190 >10000 145 28 46 >10000 146 94 25 10000 147 14 15 >10000 148 52 44 >10000 149 93 210 >10000 150 6 2 3000 151 35 21 >10000 152 20 13 >10000 153 34 12 >10000 154 100 13 3300 155 43 10 500 156 26 9 >10000 157 15 2 1200 158 83 10 5200 159 22 3 1600 160 60 20 >10000 161 17 3 4400 162 37 5 6100 163 1600 320 >10000 164 3 0.6 4300 165 6 1 4200 166 16 8 680 167 110 18 >10000 168 670 310 >10000 169 1 0.6 260 170 3 1 436 171 9 13 1100 172 4 7 3500 173 3 3 1300 174 240 250 >10000 175 19 13 >10000 176 26 18 2000 177 29 26 2300 178 34 23 2240 179 78 27 950 180 16 13 7800 181 65 77 >10000 182 18 8 7300 183 25 9 840 184 8 9 1500 185 6 4 1300 186 29 9 4300 187 15 6 2300 188 9 4 4000 189 2000 130 >10000 190 31 8 9900 191 110 51 >10000 192 62 21 4700 193 120 26 8000 194 23 20 2200 195 42 24 3800 196 19 19 6900 197 700 540 >10000 198 580 830 >10000 199 7 16 5400 200 280 160 >10000 201 3 3 1000 202 62 0.5 14 203 37 5 >10000 204 3200 310 >10000 205 2 0.7 320 206 3 2 120 207 4 2 640 208 8 6 4400 209 83 16 1800 210 37 19 6600 211 0.6 0.3 82 212 1 0.7 34 213 36 5 520 214 2 0.6 240 215 10 6 2700 216 3 0.4 40 217 0.6 0.2 83 218 210 20 >10000 219 6 1 420 220 42 7 2200 221 1100 180 >10000 222 0.6 0.2 360 223 3 3 9400 224 5 2 2100 225 537 300 >10000 226 628 270 >10000 227 9 8 5000 228 1 0.6 870 229 85 49 5000 230 7 6 1800 231 13 12 6100 232 260 190 >10000 233 >10000 10000 >10000 234 >10000 7600 >10000 235 11 12 9600 236 120 120 >10000 237 2 2 1400 238 21 15 >10000 239 3 4 2700 240 99 42 >10000 241 93 7 >10000 242 1600 220 >10000 243 200 34 3100 244 31 8 960 245 4 6 370 246 320 36 >10000 247 70 4 730 248 650 45 8600 249 3 1 160 250 160 23 2020 251 10 2 770 252 920 75 >10000 253 4 1 320 254 2 2 1400 255 150 30 >10000 256 28 15 >10000 257 5000 1500 >10000 258 7 3 3900 259 21 6 3500 260 2 0.7 220 261 49 12 5200 262 5 1 405 263 190 20 1200 264 8 2 71 265 180 31 3100 266 4 1 84 267 120 27 >10000 268 5 2 900 269 0.9 1 170 270 2300 26 >10000 271 28 18 >10000 272 1 0.9 2700 273 18 21 >10000 274 2 3 760 275 46 40 >10000 276 20 36 280 277 43 50 390 278 83 53 590 279 1 0.2 710 280 370 48 >10000 281 2 1 620 282 120 26 5700 283 3 2 740 284 340 20 >10000 285 4 1 330 286 0.8 0.3 230 287 53 8 3000 288 2 0.7 190 289 5 0.2 12 290 69 0.5 72 291 140 1 170

All of the U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification are incorporated herein by reference, in their entirety to the extent not inconsistent with the present description. From the foregoing it will be appreciated that, although specific embodiments of the invention have been described herein for purposes of illustration, various modifications may be made without deviating from the spirit and scope of the present application. 

What is claimed:
 1. A compound having the structure of formula (I):

wherein: X, Y and Z are independently selected from C(R′) or N, wherein at least one of X, Y, and Z is C(R′); n is 0, 1, 2, 3, or 4; m′ is 0 or 1; A is a single bond or C(O); each R′ is independently selected from hydrogen, halo, optionally substituted alkyl, optionally substituted haloalkyl, and optionally substituted cycloalkyl; each R¹ is independently selected from halo, cyano, optionally substituted C₁₋₆ alkyl, optionally substituted C₁₋₆ alkoxy, hydroxy, optionally substituted C₃₋₈ cycloalkyl, and optionally substituted sulfonyl; each R² is independently selected from halo, optionally substituted C₁₋₆ alkyl, optionally substituted C₁₋₆ haloalkyl, and optionally substituted C₃₋₈ cycloalkyl; R³ is hydrogen, optionally substituted C₁₋₆ alkyl, optionally substituted C₃₋₈ cycloalkyl, or optionally substituted C₆₋₁₀ aryl; R⁴ is a six- to twelve-membered heteroaryl having at least two heteroatoms, wherein each heteroatom is independently selected from N, O, or S, wherein the heteroaryl is optionally substituted with one, two, or three members independently selected from halo, cyano, —NH₂, optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkynyl; and R⁵ is hydrogen or optionally substituted C₁₋₆ alkyl; R⁵ and R³ together with the atoms to which they are attached optionally form a four- to eight-membered heterocyclic ring; or a pharmaceutically acceptable salt, isomer, or a mixture thereof.
 2. The compound of claim 1, wherein A is a single bond or C(O); each R′ is independently selected from hydrogen, halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, and C₃₋₆ cycloalkyl, wherein the alkyl moiety is optionally substituted with C₁₋₄ alkoxy; each R¹ is independently selected from halo, cyano, C₁₋₄ alkyl, C₁₋₄ haloalkyl, and —SO₂C₁₋₄ alkyl; each R² is independently selected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, and C₃₋₆ cycloalkyl, wherein the alkyl moiety is optionally substituted with C₁₋₄ alkoxy; R³ is hydrogen, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, or C₆₋₁₀ aryl; wherein the alkyl moiety is optionally substituted with hydroxyl or C₁₋₄ alkoxy, wherein C₁₋₄ alkoxy is optionally substituted with C₆₋₁₀ aryl; R⁴ is a six- to twelve-membered heteroaryl having at least one aromatic ring and at least two nitrogen atoms, wherein the heteroaryl is optionally substituted with one, two, or three members independently selected from halo, cyano, —NH₂, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, and C₁₋₄ alkyl, wherein the C₂₋₄ alkynyl moiety is optionally substituted with C₆₋₁₀ aryl or C₃₋₈ heteroaryl, wherein each of the C₆₋₁₀ aryl and C₃₋₈ heteroaryl moieties is optionally substituted with one or two members independently selected from halo and C₁₋₆ haloalkyl; and R⁵ is hydrogen or C₁₋₄ alkyl; R⁵ and R³ together with the nitrogen to which they are attached optionally form a five-membered heterocyclic ring; or a pharmaceutically acceptable salt, isomer, or a mixture thereof.
 3. The compound of claim 1, wherein each R¹ is independently selected from fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, butyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, cyano, methylsulfonyl, and ethylsulfonyl.
 4. The compound of claim 1, wherein each R² is independently selected from hydrogen, fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, butyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, methoxymethyl, methoxyethyl, ethoxymethyl, methoxypropyl, ethoxyethyl, ethoxypropyl, cyclopropyl, and cyclobutyl.
 5. The compound of claim 1, wherein R³ is selected from methyl, ethyl, propyl, cyclopropyl, cyclobutyl, phenyl, benzyloxymethyl, benzyloxyethyl, benzyloxypropyl, —CH₂OH, —C₂H₄OH, or —C₃H₆OH.
 6. The compound of claim 1, wherein R⁵ is selected from hydrogen, methyl, ethyl, or propyl.
 7. The compound of claim 1, wherein R³ and R⁵ together with the atoms to which they are attached optionally form pyrrolidinyl.
 8. The compound of claim 1, wherein R⁴ is a monocyclic heteroaryl having at least two nitrogen atoms, wherein R⁴ is optionally substituted with two or three members independently selected from the group consisting of halo, cyano, —NH₂, C₁₋₄ alkyl, and C₂₋₄ alkynyl, wherein the C₂₋₄ alkynyl moiety is substituted with C₆₋₁₀ aryl or C₃₋₈ heteroaryl, each of C₆₋₁₀ aryl or C₃₋₈ heteroaryl is optionally substituted with one or two members independently selected from halo and C₁₋₄ haloalkyl.
 9. The compound of claim 1, wherein R⁴ is a bicyclic heteroaryl having at least one aromatic ring, at least two nitrogen atoms, and at least one additional heteroatom selected from N, O, or S, wherein R⁴ is optionally substituted with one, two, or three members independently selected from the group consisting of halo, cyano, —NH₂, and C₁₋₄ alkyl.
 10. The compound of claim 1, wherein R⁴ is selected from purinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolopyrimidinyl, pyridopyrimidinyl, thienopyrimidinyl, pyrrolopyrimidinyl, furopyrimidinyl, or imidazotriazinyl; wherein each moiety is optionally substituted with one, two, or three members independently selected from the group consisting of bromo, chloro, fluoro, iodo, cyano, —NH₂, methyl, ethyl, propyl, butyl, and C₂₋₄ alkynyl, wherein the C₂₋₄ alkynyl moiety is optionally substituted with C₆₋₁₀ aryl or C₄₋₈ heteroaryl, wherein each of C₆₋₁₀ to aryl or C₃₋₈ heteroaryl is optionally substituted with one member selected from fluoro, chloro, bromo, iodo, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, and trifluoroethyl.
 11. The compound of claim 1, wherein the compound is selected from the group consisting of: (S)-2,4-diamino-6-((1-(5-chloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile; (S)-4-amino-6-((1-(5-chloro-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile; (S)-4-amino-6-((1-(5-chloro-3-(4-methyl-1H-pyrazol-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile; (S)-4-amino-6-((1-(5-chloro-3-(5-isobutyl-1H-pyrazol-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile; (S)-4-amino-6-((1-(5-chloro-3-(5-cyclopropyl-1H-pyrazol-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile; (S)-4-amino-6-((1-(5-chloro-4-oxo-3-(5-(trifluoromethyl)-1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile; (S)-4-amino-6-((1-(5-chloro-3-(5-methyl-1H-pyrazol-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile; (S)-5-chloro-3-(5-methyl-1H-pyrazol-3-yl)-2-(1-(thiazolo[5,4-d]pyrimidin-7-ylamino)ethyl)quinazolin-4(3H)-one; (S)-5-chloro-2-(1-(furo[2,3-d]pyrimidin-4-ylamino)ethyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; (S)-2-(cyclopropyl((2,6-diamino-5-chloropyrimidin-4-yl)amino)methyl)-5-fluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; (S)-2-(cyclopropyl((2,6-diamino-5-chloropyrimidin-4-yl)amino)methyl)-5,8-difluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; (S)-2-(cyclopropyl((2,6-diamino-5-chloropyrimidin-4-yl)amino)methyl)-8-fluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; (S)-8-chloro-2-(cyclopropyl((2,6-diamino-5-chloropyrimidin-4-yl)amino)methyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; (S)-5-chloro-3-(5-chloro-1H-pyrazol-3-yl)-2-(cyclopropyl((2,6-diamino-5-chloropyrimidin-4-yl)amino)methyl)quinazolin-4(3H)-one; (S)-2,4-diamino-6-((1-(5-chloro-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile; (S)-2,4-diamino-6-((1-(5-chloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile; (S)-2,4-diamino-6-(((5-chloro-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazolin-2-yl)(cyclopropyl)methyl)amino)pyrimidine-5-carbonitrile; (S)-2,4-diamino-6-(((5-chloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)(cyclopropyl)methyl)amino)pyrimidine-5-carbonitrile; (S)-5-chloro-2-(cyclopropyl((2,6-diamino-5-chloropyrimidin-4-yl)amino)methyl)-3-(1H-pyrazol-4-yl)quinazolin-4(3H)-one; (S)-5-chloro-2-(cyclopropyl((2,6-diamino-5-chloropyrimidin-4-yl)amino)methyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; (S)-2,4-diamino-6-((1-(5-chloro-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile; (S)-4-amino-6-((1-(5-chloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile; (S)-2,4-diamino-6-(2-(5-chloro-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazolin-2-yl)pyrrolidin-1-yl)pyrimidine-5-carbonitrile; (S)-2,4-diamino-6-(2-(5-chloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)pyrrolidin-1-yl)pyrimidine-5-carbonitrile; (S)-5-chloro-2-(cyclopropyl(thiazolo[5,4-d]pyrimidin-7-ylamino)methyl)-3-(1H-pyrazol-4-yl)quinazolin-4(3H)-one; (S)-5-chloro-2-(cyclopropyl(thiazolo[5,4-d]pyrimidin-7-ylamino)methyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; (S)-2-amino-4-(((5-chloro-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazolin-2-yl)(cyclopropyl)methyl)amino)-6-methylpyrimidine-5-carbonitrile; (S)-2-amino-4-(((5-chloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)(cyclopropyl)methyl)amino)-6-methylpyrimidine-5-carbonitrile; (S)-2,4-diamino-6-(((8-chloro-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazolin-2-yl)(cyclopropyl)methyl)amino)pyrimidine-5-carbonitrile; (S)-2,4-diamino-6-(((8-chloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)(cyclopropyl)methyl)amino)pyrimidine-5-carbonitrile; (S)-2,4-diamino-6-((cyclopropyl(5,8-dichloro-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazolin-2-yl)methyl)amino)pyrimidine-5-carbonitrile; (S)-2,4-diamino-6-((cyclopropyl(5,8-dichloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)methyl)amino)pyrimidine-5-carbonitrile; (S)-2,4-diamino-6-((1-(8-methyl-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile; (S)-2,4-diamino-6-((1-(8-methyl-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile; (S)-2,4-diamino-6-((1-(5-fluoro-8-methyl-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile; (S)-2,4-diamino-6-((1-(5-fluoro-8-methyl-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile; (S)-5,8-dichloro-2-(cyclopropyl(thiazolo[5,4-d]pyrimidin-7-ylamino)methyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; (S)-5,8-dichloro-2-(cyclopropyl(thiazolo[5,4-d]pyrimidin-7-ylamino)methyl)-3-(1H-pyrazol-4-yl)quinazolin-4(3H)-one; (S)-5,8-dichloro-3-(1H-pyrazol-4-yl)-2-(1-(thiazolo[5,4-d]pyrimidin-7-yl amino)propyl)quinazolin-4(3H)-one; (S)-5,8-dichloro-2-(1-(imidazo[2,1-f][1,2,4]triazin-4-ylamino)propyl)-3-(1H-pyrazol-4-yl)quinazolin-4(3H)-one; (S)-5,8-dichloro-3-(1H-pyrazol-4-yl)-2-(1-(pyrido[3,2-d]pyrimidin-4-ylamino)propyl)quinazolin-4(3H)-one; (S)-5,8-dichloro-2-(1-((6-chloropyrido[3,2-d]pyrimidin-4-yl)amino)propyl)-3-(1H-pyrazol-4-yl)quinazolin-4(3H)-one; (S)-5,8-dichloro-2-(1-(imidazo[2,1-f][1,2,4]triazin-4-ylamino)propyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; (S)-5,8-dichloro-3-(1H-pyrazol-3-yl)-2-(1-(pyrido[3,2-d]pyrimidin-4-ylamino)propyl)quinazolin-4(3H)-one; (S)-5,8-dichloro-2-(1-((6-chloropyrido[3,2-d]pyrimidin-4-yl)amino)propyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; (S)-5,8-dichloro-3-(1H-pyrazol-3-yl)-2-(1-(thiazolo[5,4-d]pyrimidin-7-ylamino)propyl)quinazolin-4(3H)-one; (R)-2-(2-(benzyloxy)-1-(thiazolo[5,4-d]pyrimidin-7-ylamino)ethyl)-5-chloro-3-(1H-pyrazol-4-yl)quinazolin-4(3H)-one; (R)-2-(2-(benzyloxy)-1-(thiazolo[5,4-d]pyrimidin-7-ylamino)ethyl)-5-chloro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; (S)-2,4-diamino-6-((1-(5-chloro-3-(5-(3-methoxypropyl)-1H-pyrazol-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile; (R)-5-chloro-2-(2-hydroxy-1-(thiazolo[5,4-d]pyrimidin-7-ylamino)ethyl)-3-(1H-pyrazol-4-yl)quinazolin-4(3H)-one; (R)-5-chloro-2-(2-hydroxy-1-(thiazolo[5,4-d]pyrimidin-7-ylamino)ethyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; (S)-2-(1-((9H-purin-6-yl)amino)propyl)-5,8-dichloro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; (S)-5,8-dichloro-2-(1-((2-fluoro-9H-purin-6-yl)amino)propyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; (S)-5,8-dichloro-3-(1H-pyrazol-3-yl)-2-(1-(thieno[2,3-d]pyrimidin-4-ylamino)propyl)quinazolin-4(3H)-one; (S)-5,8-dichloro-2-(1-((2-fluoro-9H-purin-6-yl)amino)propyl)-3-(1H-pyrazol-4-yl)quinazolin-4(3H)-one; (S)-5,8-dichloro-3-(1H-pyrazol-4-yl)-2-(1-(thieno[2,3-d]pyrimidin-4-ylamino)propyl)quinazolin-4(3H)-one; (S)-2-(1-((9H-purin-6-yl)amino)propyl)-5,8-dichloro-3-(1H-pyrazol-4-yl)quinazolin-4(3H)-one; (S)-5,8-dichloro-2-(1-((5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)propyl)-3-(1H-pyrazol-4-yl)quinazolin-4(3H)-one; (S)-5,8-dichlor-2-(1-((5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)propyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; (S)-5-chloro-3-(1H-pyrazol-3-yl)-2-(1-(thieno[2,3-d]pyrimidin-4-ylamino)ethyl)quinazolin-4(3H)-one; (S)-5-chloro-2-(1-(furo[3,2-d]pyrimidin-4-ylamino)ethyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; (S)-5,8-dichloro-2-(1-(furo[3,2-d]pyrimidin-4-ylamino)propyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; (S)-2-amino-4-chloro-6-(((5-chloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)(cyclopropyl)methyl)amino)pyrimidine-5-carbonitrile; (S)-5-chloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; (S)-5-chloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)propyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; (S)-5,8-dichloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)propyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; (S)-5-chloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-8-fluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; (S)-5-chloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)propyl)-8-fluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; (S)-5,8-dichloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; (S)-5-chloro-2-(cyclopropyl((2,6-diamino-5-chloropyrimidin-4-yl)amino)methyl)-8-fluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; (S)-5,8-dichloro-2-(cyclopropyl((2,6-diamino-5-chloropyrimidin-4-yl)amino)methyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; (S)-2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; (S)-4-oxo-3-(1H-pyrazol-3-yl)-2-(1-(thiazolo[5,4-d]pyrimidin-7-ylamino)propyl)-3,4-dihydroquinazoline-5-carbonitrile; (S)-4-oxo-3-(1H-pyrazol-3-yl)-2-(1-(thiazolo[5,4-d]pyrimidin-7-ylamino)propyl)-3,4-dihydroquinazoline-8-carbonitrile; (S)-2-(1-((2,6-diamino-5-cyanopyrimidin-4-yl)amino)propyl)-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazoline-8-carbonitrile; (S)-2-(1-((2-amino-5-cyano-6-methylpyrimidin-4-yl)amino)propyl)-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazoline-8-carbonitrile; (S)-3-(4-bromo-1H-pyrazol-3-yl)-5-chloro-2-(1-(thiazolo[5,4-d]pyrimidin-7-ylamino)propyl)quinazolin-4(3H)-one; (S)-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)propyl)-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazoline-8-carbonitrile; (S)-2-(1-((6-amino-3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)propyl)-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazoline-5-carbonitrile; (S)-2-(1-((6-amino-3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)propyl)-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazoline-8-carbonitrile; (S)-2-(1-((6-amino-3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)propyl)-5,8-dichloro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; (S)-5,8-dichloro-2-(1-((6-chlor-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)propyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; (S)-2,4-diamino-6-((1-(3-(4-bromo-1H-pyrazol-3-yl)-5-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile; (S)-2,4-diamino-6-((1-(3-(4-bromo-1H-pyrazol-3-yl)-5-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile; (S)-3-(4-bromo-1H-pyrazol-3-yl)-5,8-dichloro-2-(1-(thiazolo[5,4-d]pyrimidin-7-ylamino)ethyl)quinazolin-4(3H)-one; (S)-3-(4-bromo-1H-pyrazol-3-yl)-5,8-dichloro-2-(1-(thiazolo[5,4-d]pyrimidin-7-ylamino)propyl)quinazolin-4(3H)-one; (S)-5-(methylsulfonyl)-3-(1H-pyrazol-3-yl)-2-(1-(thiazolo[5,4-d]pyrimidin-7-ylamino)propyl)quinazolin-4(3H)-one; (S)-5,8-dichloro-2-(1-((6-chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)propyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; (S)-5-chloro-2-(1-((6-chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)ethyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; (S)-2-(1-((6-amino-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)ethyl)-5-chloro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; (S)-5-chloro-2-(1-((6-chloro-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)ethyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; (S)-2-(1-((6-amino-3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)ethyl)-5-chloro-3-(1 TH-pyrazol-3-yl)quinazolin-4(3H)-one; (S)-2-(1-((2-amino-5-cyano-6-methylpyrimidin-4-yl)amino)propyl)-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazoline-8-carbonitrile; (S)-2-(1-((6-chloropyrido[3,2-d]pyrimidin-4-yl)amino)propyl)-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazoline-8-carbonitrile; (S)-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)propyl)-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazoline-8-carbonitrile; (S)-2-(1-((2-amino-6-chloro-5-cyanopyrimidin-4yl)amino)propyl)-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazoline-8-carbonitrile; (S)-2-(1-((2,6-diamino-5-cyanopyrimidin-4-yl)amino)propyl)-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazoline-5-carbonitrile; (S)-2,4-diamino-6-((1-(5-bromo-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile; (S)-2,4-diamino-6-((1-(5-bromo-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile; (S)-5-bromo-3-(1H-pyrazol-4-yl)-2-(1-(thiazolo[5,4-d]pyrimidin-7-ylamino)propyl)quinazolin-4(3H)-one; (S)-5-bromo-3-(1H-pyrazol-3-yl)-2-(1-(thiazolo[5,4-d]pyrimidin-7-ylamino)propyl)quinazolin-4(3H)-one; (S)-2-(1-((2,6-diamino-5-cyanopyrimidin-4-yl)amino)propyl)-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazoline-5-carbonitrile; (S)-4-oxo-3-(1H-pyrazol-4-yl)-2-(1-(thiazolo[5,4-d]pyrimidin-7-ylamino)propyl)-3,4-dihydroquinazoline-5-carbonitrile; (S)-3-(4-bromo-1H-pyrazol-3-yl)-5-chloro-2-(1-(thiazolo[5,4-d]pyrimidin-7-ylamino)ethyl)quinazolin-4(3H)-one; (S)-2,4-diamino-6-(((5-chloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)(phenyl)methyl)amino)pyrimidine-5-carbonitrile; (S)-2,4-diamino-6-(((5-chloro-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazolin-2-yl)(phenyl)methyl)amino)pyrimidine-5-carbonitrile; (S)-5-chloro-2-(((2,6-diamino-5-chloropyrimidin-4-yl)amino)(phenyl)methyl)-3-(1H-pyrazol-4-yl)quinazolin-4(3H)-one; (S)-2-amino-4-(((5-chloro-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazolin-2-yl)(phenyl)methyl)amino)-6-methylpyrimidine-5-carbonitrile; (S)-5-chloro-2-(((2,6-diamino-5-chloropyrimidin-4-yl)amino)(phenyl)methyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; (S)-2-amino-4-(((5-chloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)(phenyl)methyl)amino)-6-methylpyrimidine-5-carbonitrile; (S)-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-6-fluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; (S)-2,4-diamino-6-((1-(6-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile; (S)-2,4-diamino-6-((cyclopropyl(6-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)methyl)amino)pyrimidine-5-carbonitrile; (S)-2-(cyclopropyl((2,6-diamino-5-chloropyrimidin-4-yl)amino)methyl)-6-fluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; (S)-2,4-diamino-6-((1-(6-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile; (S)-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)propyl)-6-fluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; (S)-2-amino-N-(1-(5-chloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide; (S)-3-amino-N-(1-(5,8-dichloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)propyl)pyrazine-2-carboxamide; (S)—N-(1-(5,8-dichloro-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazolin-2-yl)propyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide; (S)—N-(1-(5,8-dichloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)propyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide; (S)-3-amino-N-(1-(5-chloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)pyrazine-2-carboxamide; (S)-3-amino-N-(1-(5,8-dichloro-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazolin-2-yl)propyl)pyrazine-2-carboxamide; (S)-5-chloro-2-(1-(1-(2,6-diamino-5-chloropyrimidin-4-yl)amino)butyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; (S)-8-chloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-6-fluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; (S)-2,4-diamino-6-(((8-chloro-6-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)(cyclopropyl)methyl)amino)pyrimidine-5-carbonitrile; (S)-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-5-(difluoromethyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; (S)-2-(1-((5-bromothieno[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-chloro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; (S)-5-chloro-2-(cyclobutyl((2,6-diamino-5-chloropyrimidin-4-yl)amino)methyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; (S)-2,4-diamino-6-(((5-chloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)(cyclobutyl)methyl)amino)pyrimidine-5-carbonitrile; (S)-8-chloro-2-(cyclobutyl((2,6-diamino-5-chloropyrimidin-4-yl)amino)methyl)-6-fluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; (S)-2,4-diamino-6-(((8-chloro-6-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)(cyclobutyl)methyl)amino)pyrimidine-5-carbonitrile; (S)-2,4-diamino-6-((cyclobutyl(5-(difluoromethyl)-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)methyl)amino)pyrimidine-5-carbonitrile; (S)-2-(cyclobutyl((2,6-diamino-5-chloropyrimidin-4-yl)amino)methyl)-5-(difluoromethyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; (S)-2,4-diamino-6-((cyclopropyl(4-oxo-3-(1H-pyrazol-3-yl)-8-(trifluoromethyl)-3,4-dihydroquinazolin-2-yl)methyl)amino)pyrimidine-5-carbonitrile; (S)-2-(cyclopropyl((2,6-diamino-5-chloropyrimidin-4-yl)amino)methyl)-3-(1H-pyrazol-3-yl)-8-(trifluoromethyl)quinazolin-4(3H)-one; (S)-2,4-diamino-6-((1-(4-oxo-3-(1H-pyrazol-3-yl)-8-(trifluoromethyl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile; (S)-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-3-(1H-pyrazol-3-yl)-8-(trifluoromethyl)quinazolin-4(3H)-one; (S)-2,4-diamino-6-((1-(8-(difluoromethyl)-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile; (S)-2,4-diamino-6-((1-(6-chloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile; (S)-2,4-diamino-6-((1-(7-chloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile; (S)-2,4-diamino-6-((cyclopropyl(8-(difluoromethyl)-4-oxo-3-(1H-pyrazol-3yl)-3,4-dihydroquinazolin-2-yl)methyl)amino)pyrimidine-5-carbonitrile; (S)-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-8-(difluoromethyl)-6-fluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; (S)-2-amino-4-(difluoromethyl)-6-((1-(8-(difluoromethyl)-6-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile; (S)-2,4-diamino-6-((cyclopropyl(8-(difluoromethyl)-6-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)methyl)amino)pyrimidine-5-carbonitrile; (S)-2-(cyclopropyl((2,6-diamino-5-chloropyrimidin-4-yl)amino)methyl)-8-(difluoromethyl)-6-fluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; (S)-2-amino-4-((cyclopropyl(8-(difluoromethyl)-6-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)methyl)amino)-6-(difluoromethyl)pyrimidine-5-carbonitrile; (S)-5-chloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)-2-methylpropyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; (S)-8-chloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-5-fluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; (S)-8-chloro-2-(cyclopropyl((2,6-diamino-5-chloropyrimidin-4-yl)amino)methyl)-5-fluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; (R)-8-chloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)-2-hydroxyethyl)-6-fluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; (S)-2-(1-((5-bromothieno[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-chloro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; (S)-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-5-fluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; (S)-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-5,8-difluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; (S)-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-8-fluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; (S)-5-chloro-3-(5-chloro-1H-pyrazol-3-yl)-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)quinazolin-4(3H)-one; (S)-5-chloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-3-(5-fluoro-1H-pyrazol-3-yl)quinazolin-4(3H)-one; (S)-8-chloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; (S)-5-chloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-3-(1H-pyrazol-4-yl)quinazolin-4(3H)-one; (S)-5,8-dichloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-3-(1H-pyrazol-4-yl)quinazolin-4(3H)-one; (S)-5-chloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-8-fluoro-3-(1H-pyrazol-4-yl)quinazolin-4(3H)-one; (R)-5-chloro-2-(cyclopropyl((2,6-diamino-5-chloropyrimidin-4-yl)amino)methyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; (S)-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-6,8-difluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; (S)-2-(cyclopropyl((2,6-diamino-5-chloropyrimidin-4-yl)amino)methyl)-6,8-difluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; (S)-5-chloro-2-(1-((2,6-diaminopyrimidin-4-yl)amino)ethyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; (S)-2-(1-((6-amino-5-chloropyrimidin-4-yl)amino)ethyl)-5-chloro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; (S)-2-(((6-amino-5-chloropyrimidin-4-yl)amino)(cyclopropyl)methyl)-5-chloro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; (S)-2-amino-4-((1-(5-chloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)-6-(difluoromethyl)pyrimidine-5-carbonitrile; (S)-5-chloro-2-(1-(isothiazolo[5,4-d]pyrimidin-4-ylamino)ethyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; (S)-2-amino-4-((1-(5-chloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)-6-(trifluoromethyl)pyrimidine-5-carbonitrile; (S)-2,4-diamino-6-((1-(6,8-difluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile; (S)-2,4-diamino-6-((cyclopropyl(6,8-difluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)methyl)amino)pyrimidine-5-carbonitrile; (S)-2-amino-4-(((5-chloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)(cyclopropyl)methyl)amino)-6-(difluoromethyl)pyrimidine-5-carbonitrile; (S)-2-amino-4-(((8-chloro-6-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)(cyclopropyl)methyl)amino)-6-(difluoromethyl)pyrimidine-5-carbonitrile; (S)-2-amino-4-((1-(8-chloro-6-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)-6-(difluoromethyl)pyrimidine-5-carbonitrile; (R)-8-chloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-6-fluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; (R)-2,4-diamino-6-((1-(8-chloro-6-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile; (S)-2-amino-4-(difluoromethyl)-6-((1-(5-(difluoromethyl)-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile; (S)-2-amino-4-((cyclopropyl(5-(difluoromethyl)-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)methyl)amino)-6-(difluoromethyl)pyrimidine-5-carbonitrile; (S)-2-amino-4-(difluoromethyl)-6-((1-(4-oxo-3-(1H-pyrazol-3-yl)-5-(trifluoromethyl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile; (S)-2-amino-4-(difluoromethyl)-6-((1-(5-(difluoromethyl)-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile; (S)-2-amino-4-((1-(8-chloro-6-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)propyl)amino)-6-(difluoromethyl)pyrimidine-5-carbonitrile; (R)-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-5-(difluoromethyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; (R)-2,4-diamino-6-((1-(5-(difluoromethyl)-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile; (S)-2-amino-4-((1-(8-chloro-6-fluoro-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)-6-(difluoromethyl)pyrimidine-5-carbonitrile; (S)-2-amino-4-(((8-chloro-6-fluoro-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazolin-2-yl)(cyclopropyl)methyl)amino)-6-(difluoromethyl)pyrimidine-5-carbonitrile; (S)-2-amino-4-((1-(5-chloro-8-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)-6-(difluoromethyl)pyrimidine-5-carbonitrile; (S)-2-amino-4-(difluoromethyl)-6-((1-(8-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile; (S)-2-amino-4-((1-(6,8-difluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)-6-(difluoromethyl)pyrimidine-5-carbonitrile; (S)-2-amino-4-((1-(8-chloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)-6-(difluoromethyl)pyrimidine-5-carbonitrile; (S)-2-amino-4-(2-(5-chloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)pyrrolidin-1-yl)-6-(difluoromethyl)pyrimidine-5-carbonitrile; (S)-2-amino-4-((1-(5,8-dichloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)-6-(difluoromethyl)pyrimidine-5-carbonitrile; (S)-2-amino-4-(difluoromethyl)-6-((1-(5-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile; (S)-2-amino-4-((1-(5,8-difluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)-6-(difluoromethyl)pyrimidine-5-carbonitrile; (S)-2-amino-4-(difluoromethyl)-6-((1-(6-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile; (S)-2-amino-4-(((5-chloro-8-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)(cyclopropyl)methyl)amino)-6-(difluoromethyl)pyrimidine-5-carbonitrile; (S)-2-amino-4-((cyclopropyl(6,8-difluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)methyl)amino)-6-(difluoromethyl)pyrimidine-5-carbonitrile; (S)-2-amino-4-(((8-chloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)(cyclopropyl)methyl)amino)-6-(difluoromethyl)pyrimidine-5-carbonitrile; (S)-4-amino-6-((1-(5-chloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)-2-(difluoromethyl)pyrimidine-5-carbonitrile; (S)-4-amino-6-((1-(8-chloro-6-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)-2-(difluoromethyl)pyrimidine-5-carbonitrile; (S)-3-(5-amino-1H-pyrazol-3-yl)-5-chloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)quinazolin-4(3H)-one; (S)-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-8-(difluoromethyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; (S)-5-chloro-2-(1-((2,6-diamino-5-(trifluoromethyl)pyrimidin-4-yl)amino)ethyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; (S)-4-((1-(5-chloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)thieno[2,3-d]pyrimidine-5-carbonitrile; (S)-2-(((2-amino-5-cyano-6-methylpyrimidin-4-yl)amino)(cyclopropyl)methyl)-3-(4-methyl-1H-pyrazol-3-yl)-4-oxo-3,4-dihydroquinazoline-8-carbonitrile; (S)-2-(cyclopropyl((2,6-diamino-5-chloropyrimidin-4-yl)amino)methyl)-3-(4-methyl-1H-pyrazol-3-yl)-4-oxo-3,4-dihydroquinazoline-8-carbonitrile; (S)-2,4-diamino-6-((1-(4-oxo-3-(1H-pyrazol-3-yl)-5-(trifluoromethyl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile; (S)-2,4-diamino-6-((1-(4-oxo-3-(1H-pyrazol-4-yl)-5-(trifluoromethyl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile; (S)-2,4-diamino-6-((cyclopropyl(4-oxo-3-(1H-pyrazol-3-yl)-5-(trifluoromethyl)-3,4-dihydroquinazolin-2-yl)methyl)amino)pyrimidine-5-carbonitrile; (S)-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-3-(1H-pyrazol-3-yl)-5-(trifluoromethyl)quinazolin-4(3H)-one; (S)-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-3-(1H-pyrazol-4-yl)-5-(trifluoromethyl)quinazolin-4(3H)-one; (S)-2-(cyclopropyl((2,6-diamino-5-chloropyrimidin-4-yl)amino)methyl)-3-(1H-pyrazol-3-yl)-5-(trifluoromethyl)quinazolin-4(3H)-one; (S)-2,4-diamino-6-((1-(5-(difluoromethyl)-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile; (S)-2,4-diamino-6-((1-(5-(difluoromethyl)-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile; (S)-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-5-(difluoromethyl)-3-(1H-pyrazol-4-yl)quinazolin-4(3H)-one; (S)-2,4-diamino-6-((cyclopropyl(5-(difluoromethyl)-4-oxo-3-(1H-pyrazolo-3-yl)-3,4-dihydroquinazolin-2-yl)methyl)amino)pyrimidine-5-carbonitrile; (S)-2-(cyclopropyl((2,6-diamino-5-chloropyrimidin-4-yl)amino)methy)-5-(difluoromethyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; (S)-2,4-diamino-6-((1-(5-chloro-3-(3-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile; (S)-2,4-diamino-6-((1-(5,8-dichloro-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile; (S)-5,8-dichloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-3-(3-methyl-1H-pyrazol-4-yl)quinazolin-4(3H)-one; (S)-2,4-diamino-6-((1-(5,8-dichloro-3-(3-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile; (S)-2,4-diamino-6-(((8-chloro-6-fluoro-3-(3-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)(cyclopropyl)methyl)amino)pyrimidine-5-carbonitrile; (S)-8-chloro-2-(cyclopropyl((2,6-diamino-5-chloropyrimidin-4-yl)amino)methyl)-6-fluoro-3-(3-methyl-1H-pyrazol-4-yl)quinazolin-4(3H)-one; (S)-2,4-diamino-6-((1-(8-chloro-5-methyl-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile; (S)-8-chloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-5-methyl-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; (S)-2-amino-4-((1-(8-chloro-5-methyl-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)-6-(difluoromethyl)pyrimidine-5-carbonitrile; (S)-2-(1-((2-amino-5-chloro-6-(difluoromethyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; (S)-2-(1-((2-amino-5-chloro-6-(difluoromethyl)pyrimidin-4-yl)amino)ethyl)-8-chloro-6-fluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; (S)-8-chloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-5-(difluoromethyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; (S)-2,4-diamino-6-((1-(8-chloro-5-(difluoromethyl)-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile; (S)-6-chloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-5-(difluoromethyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; (S)-2,4-diamino-6-((1-(6-chloro-5-(difluoromethyl)-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile; (S)-2,4-diamino-6-((1-(7,8-difluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile; (S)-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-7,8-difluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; (S)-2-(1-((2-amino-5-chloro-6-(difluoromethyl)pyrimidin-4-yl)amino)ethyl)-5,7-difluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; (S)-2-(1-((2-amino-5-chloro-6-(difluoromethyl)pyrimidin-4-yl)amino)ethyl)-7,8-difluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; (S)-2,4-diamino-6-((1-(5,7-difluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile; (S)-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-5,7-difluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; (S)-2,4-diamino-6-((1-(5-chloro-7-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile; (S)-5-chloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-7-fluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; (S)-2,4-diamino-6-(((5-chloro-7-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)(cyclopropyl)methyl)amino)pyrimidine-5-carbonitrile; (S)-5-chloro-2-(cyclopropyl((2,6-diamino-5-chloropyrimidin-4-yl)amino)methyl)-7-fluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; (S)-2-(cyclopropyl((2,6-diamino-5-cyanopyrimidin-4-yl)amino)methyl)-3-(4-methyl-1H-pyrazol-3-yl)-4-oxo-3,4-dihydroquinazoline-8-carbonitrile; 2-((1 S)-((6-amino-3-bromo-3aH-pyrazolo[3,4-d]pyrimidin-4-yl)amino)(cyclopropyl)methyl)-5-chloro-3-(4-methyl-1H-pyrazol-3-yl)quinazolin-4(3H)-one; (S)-5-chloro-2-(cyclopropyl((2,6-diamino-5-chloropyrimidin-4-yl)amino)methyl)-3-(4-methyl-1H-pyrazol-3-yl)quinazolin-4(3H)-one; (S)-2-amino-4-chloro-6-(((5-chloro-3-(4-methyl-1H-pyrazol-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)(cyclopropyl)methyl)amino)pyrimidine-5-carbonitrile; (S)-2-amino-4-(((5-chloro-3-(4-methyl-1H-pyrazol-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)(cyclopropyl)methyl)amino)-6-methylpyrimidine-5-carbonitrile; (S)-2,4-diamino-6-((1-(5-cyclopropyl-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile; (S)-2-(((2-amino-6-chloro-5-cyanopyrimidin-4-yl)amino)(cyclopropyl)methyl)-3-(4-methyl-1H-pyrazol-3-yl)-4-oxo-3,4-dihydroquinazoline-8-carbonitrile; (S)-2,4-diamino-6-(((5-chloro-3-(4-methyl-1H-pyrazol-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)(cyclopropyl)methyl)amino)pyrimidine-5-carbonitrile; (S)-2,4-diamino-6-((1-(5-chloro-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazolin-2-yl)butyl)amino)pyrimidine-5-carbonitrile; (S)-5-chloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)butyl)-3-(1H-pyrazol-4-yl)quinazolin-4(3H)-one; (S)-2,4-diamino-6-((1-(5,8-dichloro-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazolin-2-yl)butyl)amino)pyrimidine-5-carbonitrile; (S)-5,8-dichloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)butyl)-3-(1H-pyrazol-4-yl)quinazolin-4(3H)-one; (S)-2,4-diamino-6-((1-(5-chloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)butyl)amino)pyrimidine-5-carbonitrile; (S)-2,4-diamino-6-((1-(5,8-dichloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)butyl)amino)pyrimidine-5-carbonitrile; (S)-5,8-dichloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)butyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; (S)-8-chloro-2-(cyclopropyl((2,6-diamino-5-chloropyrimidin-4-yl)amino)methyl)-6-fluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; (S)-8-chloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)propyl)-6-fluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; (S)-2,4-diamino-6-((1-(8-chloro-6-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile; (S)-5-chloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-6-fluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; (S)-2,4-diamino-6-((1-(5-chloro-6-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile; (S)-5-chloro-2-(cyclopropyl((2,6-diamino-5-chloropyrimidin-4-yl)amino)methyl)-6-fluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; (S)-2,4-diamino-6-(((5-chloro-6-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)(cyclopropyl)methyl)amino)pyrimidine-5-carbonitrile; (S)-5-chloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-6-fluoro-3-(1H-pyrazol-4-yl)quinazolin-4(3H)-one; (S)-2,4-diamino-6-((1-(5-chloro-6-fluoro-4-oxo-3-(1H-pyrazolo-4-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile; (S)-8-chloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-6-fluoro-3-(1H-pyrazol-4-yl)quinazolin-4(3H)-one; (S)-2,4-diamino-6-((1-(8-chloro-6-fluoro-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile; (S)-5-chloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)butyl)-6-fluoro-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; (S)-2,4-diamino-6-((1-(5-chloro-6-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)butyl)amino)pyrimidine-5-carbonitrile; (S)-2,4-diamino-6-(((8-chloro-6-fluoro-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazolin-2-yl)(cyclopropyl)methyl)amino)pyrimidine-5-carbonitrile; (S)-3-(4-bromo-1H-pyrazol-3-yl)-8-chloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-6-fluoroquinazolin-4(3H)-one; (S)-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-6-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazoline-8-carbonitrile; (S)-2-(1-((2,6-diamino-5-cyanopyrimidin-4-yl)amino)ethyl)-6-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazoline-8-carbonitrile; (S)-2-(cyclopropyl((2,6-diamino-5-chloropyrimidin-4-yl)amino)methyl)-6-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazoline-8-carbonitrile; (S)-2,4-diamino-6-((1-(4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile; (S)-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-3-(1H-pyrazol-3-yl)quinazolin-4(3H)-one; (S)-3,5-diamino-6-chloro-N-(1-(5-chloro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)pyrazine-2-carboxamide; (S)-3,5-diamino-6-chloro-N-(1-(5-chloro-8-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)pyrazine-2-carboxamide; (S)-3,5-diamino-6-chloro-N-(1-(5-chloro-8-fluoro-4-oxo-3-(1H-pyrazol-4-yl)-3,4-dihydroquinazolin-2-yl)ethyl)pyrazine-2-carboxamide; (S)-2,4-diamino-6-((1-(8-chloro-6-fluoro-4-oxo-3-(1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile; (S)-8-chloro-2-(cyclopropyl((2,6-diamino-5-chloropyrimidin-4-yl)amino)methyl)-6-fluoro-3-(1H-imidazol-4-yl)quinazolin-4(3H)-one; (S)-2,4-diamino-6-(((8-chloro-6-fluoro-3-(1H-imidazol-4-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)(cyclopropyl)methyl)amino)pyrimidine-5-carbonitrile; (S)-5-chloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)butyl)-3-(1H-imidazol-4-yl)quinazolin-4(3H)-one; (S)-2,4-diamino-6-((1-(5-chloro-3-(1H-imidazol-4-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)butyl)amino)pyrimidine-5-carbonitrile; (S)-8-chloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-6-fluoro-3-(1H-imidazol-4-yl)quinazolin-4(3H)-one; (S)-2,4-diamino-6-((1-(8-chloro-6-fluoro-3-(1H-imidazol-4-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile; (S)-2,4-diamino-6-((1-(5,8-dichloro-3-(1H-imidazol-4-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile; (S)-5-chloro-2-(cyclopropyl((2,6-diamino-5-chloropyrimidin-4-yl)amino)methyl)-3-(1H-imidazol-4-yl)quinazolin-4(3H)-one; (S)-2,4-diamino-6-((1-(5-chloro-3-(1H-imidazol-4-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile; (S)-2,4-diamino-6-((1-(5-chloro-4-oxo-3-(1H-pyrrol-2-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile; (S)-2,4-diamino-6-((1-(5-chloro-4-oxo-3-(1H-pyrrol-2-yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile; and (S)-5-chloro-2-(1-(imidazo[2,1-f][1,2,4]triazin-4-ylamino)ethyl)-3-(1H-pyrrol-2-yl)quinazolin-4(3H)-one; or a pharmaceutically acceptable salt, isomer, or a mixture thereof.
 12. The compound of claim 1, wherein the compound is an atropisomer.
 13. A pharmaceutical composition comprises the compound of claim 1 and at least one pharmaceutically acceptable vehicle.
 14. A method of treating a disease or condition in a human in need thereof comprises the administering to the human a therapeutically effective amount of the compound of claim 1, wherein the disease or condition is selected from cancer, hematologic malignancies, leukemias, lymphomas, myeloproliferative disorders, myelodysplastic syndromes, plasma cell neoplasms, solid tumor, inflammation, fibrosis, autoimmune disorders, allergic conditions, hypersensitivity, cardiovascular diseases, neurodegenerative diseases, renal disorders, viral infections, obesity, and autoimmune diseases.
 15. The method of claim 14, wherein the disease or condition is selected from rheumatoid arthritis, osteoarthritis, atherosclerosis, psoriasis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, asthma, chronic obstructive airways disease, pneumonitis, dermatitis, alopecia, nephritis, vasculitis, atherosclerosis, Alzheimer's disease, hepatitis, primary biliary cirrhosis, sclerosing cholangitis, diabetes (including type I diabetes), acute rejection of transplanted organs, lymphomas, multiple myelomas, leukemias, pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, prostate cancer, renal cancer, hepatocellular cancer, lung cancer, ovarian cancer, cervical cancer, rectum cancer, liver cancer, kidney cancer, stomach cancer, skin cancer, gastric cancer, esophageal cancer, head and neck cancer, melanoma, neuroendocrine cancers, CNS cancers (e.g., neuroblastoma), brain tumors (e.g., glioma, anaplastic oligodendroglioma, adult glioblastoma multiforme, and adult anaplastic astrocytoma), bone cancer, or soft tissue sarcoma. In some embodiments, the solid tumor is non-small cell lung cancer, small-cell lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, pancreatic cancer, prostate cancer, and breast cancer.
 16. A method of inhibiting the activity of a phosphatidylinositol 3-kinase polypeptide by contacting the polypeptide with the compound of claim
 1. 17. A method of inhibiting excessive or destructive immune reactions or growth or a proliferation of cancer cells, comprising administering an effective amount of the compound of claim
 1. 18. A kit comprises die compound of any of claim 1 or a label and/or instructions for use.
 19. The compound, a pharmaceutically acceptable salt, isomer, or a mixture thereof of claim 1 for use in therapy.
 20. The compound, a pharmaceutically acceptable salt, isomer, or a mixture thereof of claim 1 for use in a method of treating of claim
 16. 21. Use of the compound, a pharmaceutically acceptable salt, isomer, or a mixture thereof of claim 1 for the manufacture of a medicament for treatment of a disease or condition of claim
 16. 